Compositions comprising hyaluronic acid and drugs

ABSTRACT

A dosage amount of a pharmaceutical composition comprising a therapeutically effective amount of an agent to treat a disease or condition involving underperfused tissue and pathological tissue in humans and a form of hyaluronic acid, wherein the form of hyaluronic acid is available to transport the agent from the point of administration to the site to be treated.

This application is a divisional of application Ser. No. 07/675,908,filed Jul. 3, 1991 which was filed as application No. PCT/CA90/00306,filed Sep. 18, 1990.

FIELD OF THE INVENTION

The invention relates to, formulations suitable for use to treatconditions and disease, (for example cancer), the use of suchformulations to treat conditions and disease, methods of treatingconditions and disease, and the delivery of medicinal and therapeuticagents for the treatment of disease and conditions.

BACKGROUND OF THE INVENTION

In an article entitled "Solid cores of tumors keeping out best drugs" bySandra Blakeslee published in the Jul. 8, 1989 edition of the Globe andMail, Toronto, Ontario, Ms. Blakeslee submitted that a growing number ofresearchers believe that a basic misunderstanding of the structure ofsolid tumors has led researchers into designing cancer drugs that aredoomed to fail in many patients.

She relates that, Dr. Herberman, Director of the Pittsburgh CancerCenter, said that for decades, cancer researchers have simply developeddrugs, put them in the bloodstream and assumed they would be carried tothe tumor giving almost no consideration to how uniformly the drug isdistributed once it reaches the tumor.

Her article also provided that according to Dr. Judah Folkman, a leadingresearcher on blood growth factors at the Harvard Medical School, for along time, physicians have been taught that tumors outgrow theirblood-supply. According to the article that statement is not true.Tumors compress their blood supply. This compression makes it harder toadminister drugs.

The article provides further that most people think a tumor is nothingbut a collection of cancer cells. According to Dr. Jain, anotherresearcher, in reality the tumor is only 50 per cent cells. The otherhalf is blood vessels and interstitial space. Interstitial space in atumor, he said, can be likened to the space between marbles packed in abox.

The article further provides that no matter how biological agents aremixed and administered, they must cross a blood-vessel wall and thencross the interstitium to reach their targets, cancer cells. The articlecontinues that every tumor is different and there are different regionswithin each. Moreover, tumors change daily as they grow and rearrangeparts. Most blood vessels inside tumors are highly disorganized as theytake tortuous turns and grow peculiar attachments to nearby vessels.

In general, Dr. Jain said, as a tumor grows, its outer region recruitsnew blood vessels from surrounding normal tissue. It also forms severalabnormal blood vessels of its own. As the tumor grows in a confinedspace, many of the twisted blood vessels near its center are crushed. Inturn, the tumor cells near them appear to die, although they grow intoactive cancer if transplanted in other animals. High pressures build upin these necrotic regions. Both blood vessels and liquid plasma in theinterstitial spaces are squeezed. The pressure, therefore, preventsblood-borne molecules, including oxygen, from entering the central tumorareas.

Pressure is not uniform in normal tissue, Dr. Jain said, so a largemolecule such as an antibody would reach its target through convectioninduced by pressure differences. But in the center of a tumor, pressureis uniformly high, blocking convection.

Molecules also migrate by diffusion Dr. Jain said, which is similar tothe way a drop of ink spreads in water.

But he indicated that he measured antibody diffusion in tumors and foundthat it can take days, weeks or months for such large molecules to reachuniform concentration by diffusion in tumors. By then, it may be toolate for treatments to do any good.

Finally, the fluid that builds up in the interstitium slowly leaks outof the tumor, he said, washing away molecules trying to reach itscenter.

In our Canadian Patent Application Ser. No. 568,512 we disclose a newformulation suitable for use for treating cancer (for use in conjunctionwith at least thermotherapy (hyperthermia) and if desired, othermodalities (such as chemotherapy or radiation)), the formulationcomprising (for example in a pharmaceutically acceptable carrier):

(a) a glucose inhibiting (non-toxic) amount of an agent that blocks theglucose transport protein (active transport molecule in the membrane) ofa cell from transporting glucose into the cell, and

(b) an effective (non-toxic) amount of an agent which (i) enhancespenetration and transport of agent (a) through the tissue surroundingthe various cellular elements, generally known as scar tissue or fibrousreaction around the..cancerous tumor, and (ii) alters thepenetration-characteristics of the tissue surrounding the tumor topermit agent (a) to be transported to the center of the tumor.

We also disclosed a combination and formulation suitable for use fortreating cancer, the combination comprising:

(a) a glucose inhibiting (non-toxic) amount to an agent that blocks theglucose transport protein (active transport molecule in the membrane) ofa cell from transporting glucose into the cell, and

(b) an effective (non-toxic) amount of an agent which (i) enhancespenetration and transport of agent (a) through the tissue surroundingthe various cellular elements, generally known as scar tissue or fibrousreaction around the cancerous tumor, and (ii) alters the penetrationcharacteristics of the tissue surrounding the tumor to permit agent (a)to be transported to the center of the tumor.

After the introduction of the formulation or combination comprisingagents (a) and (b) to the patient which have the effect of metabolicallycompromising the cancer cells of the tumor, the tumor and the cancercells making up the tumor are stressed by at least thermotherapy(hyperthermia). In this regard, when agent (a) is transported into thetumor cells and the tumor cells are stressed, there is an inadequateamount of glucose available to the tumor cells for them to continue tofunction metabolically. Thus the tumor cell is impaired in its energysupply and dies. We also disclosed in the application a method for thetreatment of cancer which method comprises administering (for example ina pharmaceutically acceptable carrier):

(a) a glucose inhibiting (non-toxic) amount of an agent that blocks theglucose transport protein (active transport molecule in the membrane) ofa cell from transporting glucose into the cell, and

(b) an effective (non-toxic) amount of an agent which (i) enhancespenetration and transporting of agent (a) through the tissue surroundingthe various cellular elements, generally known as scar tissue or fibrousreaction around the cancerous tumor, and (ii) alters the penetrationcharacteristics of the tissue surrounding the tumor to permit agent (a)to be transported to the center of the tumor, and subjecting the cancercells to hyperthermia (thermotherapy) therapy. In some instances othermodalities (for example chemotherapy and/or radiation therapy) may alsobe employed.

The glucose inhibiting (non-toxic) amount of the agent that blocks theglucose transport protein of a cell from transporting glucose into thecell (in cancer cells there appear to be more than in normal cells) maycomprise: ##STR1## or their analogues including phlorizin glucuronide;4-deoxy-phloretin-2-D-glucoside and the like.

The effective (non-toxic) amount of the agent which

(i) enhances penetration and transport of agent (a) through the tissuesurrounding the various cellular elements generally known as scar tissueor fibrous reaction around the cancerous tumor, and

(ii) alters the penetration characteristics of the tissue surroundingthe tumor to permit agent (a) to be transported to the center of thetumor may comprise dimethyl sulfoxide (DMSO), methylsulfonylmethane(MSM) (also called methylsulfone methane) or other carriertransport-type molecules having the characteristics which

(i) enhances penetration and transport of agent (a) through the tissuesurrounding the various cellular elements, generally known as scartissue or fibrous reaction around the cancerous tumor, and

(ii) alters the penetration characteristics of the tissue surroundingthe tumor to permit agent (a) to be transported to the center of thetumor.

In the publication Ontario Medicine, Volume 8, No. 16 dated Aug. 21,1989 the article "Toxic drug tamed but still potent" describes how anexperimental liposomal drug delivery system, is used to encapsulate ahighly toxic but highly effective anti-fungal agent, demonstrating thatnoxious drugs can be transformed into non-toxic agents withoutcompromising clinical efficacy.

The article concluded as follows:

"It was initially hoped that liposomes would offer considerablepotential as a drug delivery system for almost all pharmaceuticalagents. However, research into the drug delivery system over the pasttwo decades has shown that the artificial, cell-sized spheres formspontaneously with only a small subset of drugs available today thuslimiting their use."

Hoffer in a study explored the effects of ascorbic acid (Vitamin C) inrespect of the health of patients. In the article he discussed theeffects of Vitamin C with respect to cancer treatment. He also discussedthe findings of Cameron and Pauling of the use of ascorbic acid in 10gram doses to treat cancer patients and which administration of theascorbic acid increased the survival of terminally ill cancer patients.He also discussed the safety of the use of ascorbic acid and the safetyin very high doses. He stated at page 11 of his study that the ascorbicacid was water soluble, was bulky but had no LD-50. Hoffer states that

"When the vitamin cannot be absorbed completely from thegastrointestinal system, it will remain water in the bowel leading todiarrhea, which is watery but not dangerous unless it causesdehydration; it quicky forces patients to decrease the doses. It has andis being used by millions of people in these doses. Patients I haveknown have taken 30 grams per day for 30 years. It is safer than commontable salt, gram for gram. It does not cause kidney stones, does notcause pernicious anemia, does not make women infertile, does not causecancer."

It is therefore an object of this invention to provide formulationssuitable for use to treat disease and conditions, the use of suchformulations to treat disease and conditions, methods of treatingdisease and conditions and the delivery of medicinal and therapeuticagents for the treatment of disease (for example, cancer) andconditions.

Further and other objects of the invention will be realized by thoseskilled in the art from the following disclosure and in which Applicantsrefer to literature uncovered after the date of their invention.

Hyaluronic acid is a naturally occurring glycosaminoglucan. Itsmolecular weight may vary from 50,000 dalton upwards, and it formshighly viscous solutions. As regards the actual molecular weight ofhyaluronic acid in natural biological contexts, this is still a matterof much uncertainty: When the molecular weight of hyaluronic acid is tobe determined, different values are obtained depending on the assaymethod employed, and on the source, the isolation method etc. The acidoccurs in animal tissue, e.g. spinal fluid, ocular fluid, synovialfluid, cockscombs, skin, and also in some streptococci. Various gradesof hyaluronic acid have been obtained. A preparation with an allegedlyhigh degree of purity and alleged to be entirely free from side effects,is a non-inflammatory form described in U.S. Pat. No. 4,141,973; thispreparation is said to have a molecular weight exceeding 750,000 dalton,:preferably exceeding 1,200,000 dalton and is suggested for therapeuticuse in various articular conditions.

U.S. Pat. No. 4,801,619 relates to hyaluronic acid administeredintra-articularly having a molecular weight of about 3×10⁶ dalton ormore, which is prone to decrease the proteoglycan content of synovialfluid to almost normal levels. According to this patent, this indicatesa positive effect on the proteoglycan metabolism of a joint. Accordingto the Patent this is applicable both to inflammatory conditions and todegeneration caused by treatment with symptomatics, such ascorticosteroid preparations. It is thus clear that a sufficiently highmolecular weight of the hyaluronic acid is alleged to counteract sideeffects that might be caused by corticosteroids or other symptomaticsproducing similar effects. When corticosteroids are applied, the amountof hyaluronic acid in the synovial cavity will according to the Patentincrease substantially and according to the inventors their hyaluronicacid preparations have a very positive effect on such clinical symptomsas pain, swelling and lameness.

The patent states that the objectives of the invention are attained byintra-articular administration of an effective amount of hyaluronic acidwith a mean molecular weight exceeding 3×10⁶ dalton, preferablyexceeding 4×10⁶ dalton; usually the molecular weight will not exceed7×10⁶ dalton. The dosage of hyaluronic acid administered is stated to bepreferably within the range of 5 mg-80 mg. The amount of solution givenat each administration is generally less than 60 ml, e.g. less that 20ml, of an aqueous solution of the acid or its salt. It is convenient toadminister the acid dissolved in water (<2% w/w, buffered tophysiological pH), for instance in the form of a water-soluble sodiumsalt. The exact amount will depend on the particular joint to betreated.

The Merck Index Specifies that Hyaluronic Acid has a Molecular Weightwithin the range pf 50,000 to 8×10⁶ depending on source, methods ofpreparation and methods of determination. The Merck Publication teacheshyaluronic acid as a surgical aid (ophthalmological).

U.S. Pat. No. 4,808,576 purports to teach that hyaluronic acid, an agentwell known to reduce the sequelae of trauma in mammalian joint tissuewhen applied directly to the traumatized tissue, will be carried to suchtraumatized tissue by the mammal's natural processes if applied at asite remote from the traumatized tissue. Thus hyaluronic acid in anytherapeutically acceptable form can, according to the Patent, beadministered by the typical remote routes including intravenous,intramuscular, subcutaneous and topical.

This, the patent alleges, makes the utilization of hyaluronic acid muchmore convenient and attractive. For instance the treatment of arthritisin horse or human joints with hyaluronic acid according to the patent nolonger requires more difficult intra articular injections.

U.S. Pat. No. 4,725,585 relates to a method of enhancing or regulatingthe host defence of a mammal, said method comprising administering to amammal a therapeutically effective amount of hyaluronic acid.

At column 1 lines 43-46, the patent provides that the invention wasbased on the unexpected discovery that administration of hyaluronic acidto mammals results in a considerable increase in the defence.

The hyaluronic acid employed in the Patent was Healon (T. M.) providedby Pharmacia A B, Uppsala, Sweden (Pharmacia A B is also entitled to thebenefit of U.S. Pat. No. 4,141,973). The patent provides at column 4,line 19 that because a patient's infections had been hard to treat,instead of just hyaluronic acid being administered to the patient toincrease the patient's defence, the patient was given hyaluronic acidand an antibiotic. While the patent states that the antibiotic was givenin combination with hyaluronic acid, in fact because the hyaluronic acidwas administered subcutaneously and because the patient was a heartpatient, one skilled in the art would understand that any antibioticadministered, while possibly administered simultaneously was definitelyadministered separately intravenously (probably) or intramuscularly(less probably). Thus, (most probably) the hyaluronic acid administeredaccording to the teachings of this patent was administered in order toprevent possible development of infections (increase the host's defence)and not for any other reason.

U.S. Pat. No. 4,636,524 discloses cross-linked gels of hyaluronic acid,alone and mixed with other hydrophilic polymers and containing varioussubstances or covalently bonded low molecular weight substances andprocesses for preparing them. These products are alleged to be useful innumerous applications including cosmetic formulations and as drugdelivery systems.

The patent further states that as hyaluronic acid is known to be abiologically tolerable polymer in the sense that it does not cause anyimmune or other kind of response when introduced into a human body, thecross-linked hyaluronic acid gels can be used for various medicalapplications. The cross-linked gels modified with other polymers or lowmolecular weight substances it is alleged can be used as drug deliverydevices. For example, the inventors are alleged to have found thatheparin introduced in a cross-linked hyaluronic acid gel retained itsantithrombogenic activity.

The inventors also allege that they have also found that cross-linkedgels of hyaluronic acid can slow down the release of a low molecularweight substance dispersed therein but not covalently attached to thegel macromolecular matrix.

U.S. Pat. No. 4,736,024 purports to teach new medicaments for topicaluse containing:

(i) an active pharmacological substance or a mixture of pharmacologicalsubstances, either active or suitable for topical administration and

(ii) a topical vehicle which comprises hyaluronic acid or a molecularfraction of hyaluronic acid or a salt of the same with an alkalinemetal, an alkaline earth metal, magnesium, aluminium, ammonium or apharmacological substance, optionally together with additionalconventional excipients for pharmaceutical preparations for topical use.

Applicants are also aware of recently published Japanese Patent Document61000017 dated Jan. 6, 1986 whose English abstract of disclosure statesthat the Japanese Patent Document relates to the use of hyaluronic acidor cross-linked hyaluronic acid or their salts as the active ingredientfor inhibiting carcinoma metastasis.

According to the purported abstract of the Patent more that 1.0% ofhyaluronic acid is dissolved in alkaline aq. soln. and pref. more than50% of H₂ O sol. org. solvent. eq. alcohol, acetone, dioxane, againsttotal soln. is added. Preferably the pH is 12-14. Then multifunctionalepoxy cpd. is added and reacted at 10-60 deg. C., pref. at 20-40- deg.C. for 24 hrs. Cross-linking ratio of crosslinked hyaluronic acid or itssalt is regulated by changing mol ratio of hyaluronic acid or its saltand multifunctional epoxy cpd.. Pref. hyaluronic acid used has intrinsicviscosity 0.2-30, m.w. 4000-2000000. The hyaluronic:acid is allegedlyused in several dosage forms. Clinical dose for adult is alleged to benormally, as hyaluronic acid or cross-linked hyaluronic acid, 25 m-5g/day (p.o.) and 10 mg-2.5 g/l dose (inj). The abstract alleges that theadvantage is that the hyaluronic acid has no side effects as otheranticancer drugs and has an analgesic and a tissue restoration effect.

European Patent Application 0295092 purports to teach a vehicle togetherwith fragments of hyaluronic acid for delivering of the fragments ofhyaluronic acid into the skin to reach the dermal layer of the skin toincrease the development of blood vessels for stimulating hair growth orregrowth. The preferred fragments of hyaluronic acid are polysaccharidescontaining from 7 to 25 monosaccharide units. The patent provides it isapparent that the larger the fragments of hyaluronic acid, the greaterthe difficulty there is in delivering the fragments to the dermal layerof the skin, unless there is also present in the composition a means forenhancing the activity of said fragments.

The combination may thus include a means for enhancing the activity ofthe fragments of hyaluronic acid especially to improve their penetrationthrough the skin following topical application. Some activity enhancers,it is alleged, also function as vehicles for the fragments of thehyaluronic acid.

Some activity enhancers are also alleged to possess the ability tostimulate or increase hair growth. Minoxidil is asserted among others tobe such an activity enhancer. Thus both the fragments of hyaluronic acidand minoxidil are alleged to stimulate hair growth both delivered by avehicle.

European Patent Application 0179442 asserts that where free radicals areformed in considerable quantities, hyaluronic acid is broken down ordegraded before the hyaluronic acid has given the desired effect.

Canadian Letters Patent 1,240,929 teaches the combination of chondroitinsulfate compound and a hyaluronate to protect both human and animal celllayers and tissue subject to exposure to trauma.

European Patent Application 0208623 purports to teach hyaluronic acid asune augmentation de l'activite de certaines proteases. It also purportsto teach the use of hyaluronic acid for treating connective tissuediseases including malignant tumors and cardiovascular disorders.

European Patent Application 270317 purports to teach the combination ofan antiviral agent lacking inhibitory action and a compound (forexample, hyaluronic acid) possessing cell fusion inhibitory activityand/or virus-adsorption inhibitory activity for treating disease carriedby a virus.

U.S. Pat. No. 4,840,941 purports to teach the use of an effective amountof hyaluronic acid as the active agent for the treatment of retrovirusesin association with a pharmaceutically acceptable carrier, diluent orexcipient.

U.S. Pat. No. 4,851,521 and European Patent Application 0265116 bothdescribe hyaluronic acid fractions, the making thereof and cross-linkedesters of hyaluronic. U.S. Pat. No. 4,851,521 describes esters ofhyaluronic acid incorporated into pharmaceutical preparations as theactive ingredient and as vehicles for ophthamological medicines fortopical use (See column 11, lines 35 to 42; and column 12, lines 62 tocolumn 13, line 3) and in suppositories for a systemic effect due to theeffect of transcutaneous absorption, such as in suppositories.

The patent provides at column 13, lines 5 to 31: "The vehicling actionof the hyaluronic esters also applies to associated medicaments of thetype mentioned above in which the active substance acts not onlytopically or by nasal or rectal absorption, for example by nasal spraysor preparations for inhalation for the oral cavity or the pharynx, butalso by oral or parenteral route, for example by intramuscular,subcutaneaous or intravenous route, as it favors absorption of the druginto the application site. The new medicaments can therefore be applied,apart from in the fields already mentioned, in practically all sectorsof medicine, such as internal medicine, for example in pathologies ofthe cardiovascular system, in infections of the respiratory system, thedigestive system, the renal system, in diseases of an endocrinologicalnature, in oncology, in psychiatry etc., and may also be classifiedtherefore from the point of view of their specific action, being perhapsanesthetics, analgesics, anti inflammatories, wound healers,antimicrobics, adrenergic agonsits and antagonists, cytostatics,antirheumatics, antihypertensives, diuretics, sexual hormones,immunostimulants and immunosuppressants, for example, one of the drugshaving the activity already described for the therapeutically activealcohols to be used as esterifying component according to the presentinvention, or for the therapeutically active bases used for thesalification of the free carboxylic groups."

Furosemide inhibits sodium reabsorption in the ascending limb of Henle'sLoop and in both proximal and distal tubules. The action of the drug isindependent of any inhibitory affect on carbonic anhydrase oraldosterone. Furosemide is known to promote diuresis in cases which havepreviously proved resistant to other diuretics. It has no significantpharmalogical effects other than on renal function. In the human it isabsorbed from the gastrointestinal tract. Following intravenousadministration a diuresis generally occurs within 30 minutes and theduration of action is about 2 hours.

Under a variety of circumstances, the patient can become relativelyresistant to the effects of Lasix. This can be so for a variety ofreasons but is certainly seen in those situations where there is a majoramount of peripheral edema or "third spacing" of fluid which may be truein malnutrition and/or advanced carcinomas. In the latter instances,there is a markedly decreased level of albumin and in all probability,increased permeability and transudation of fluid out of the vascularsystem. Hence, these patients can become relatively resistant to any ofthe diuretics including high doses of Lasix administered intravenously.

There have been extensive studies to determine the defect in immunefunction that allows a tumor cell to develop. It was postulatedinitially by Jerne, and subsequently by Burnett that the immune system'smajor role was that of immunological surveillance to destroy abnormalcells. The concept of surveillance, while somewhat simplistic, remainsan accepted concept for the elaborate mechanism of immune recognitionand function that is present in the higher species--mammals.

It has then been postulated that tumors develop because of local orgeneralized immune suppression. However, as pointed out by Moller, ifgeneral immune suppression occurs, it is only certain types ofneoplastic disorders that develop, mainly those of the lympho-reticularsystem. This observation is correct and represents a major challenge tothe immune surveillance theory unless a specific reason can be shown asto why the individual cancer cell can develop plus individually evadethe immune system.

It was demonstrated experimentally in 1974 that defects of macrophagefunction may exist in neoplastic disease.

The initial experiments found suppressor cells to be part of the immunesystem; these were either of the T-cell type of the macrophage cellsystem. There was presence demonstrated in neoplasia, chronic bacterialinfection, recovery from massive injury and chronic fungal infection.

There has been repeated demonstration in experimental animals, that themacrophage cell function is altered in neoplastic disease. Themacrophages in the animal's systems appeared "blocked" in theirfunction. Generally when removed from the in vivo situation, washed insaline and cultured, they could perform normally. This block has beenshown to be related to the excessive production of prostaglandin byneoplastic tissue or by the macrophage itself.

In the basic research efforts in the latter '70s and the early 80's,there existed considerable confusion as to what role immunotherapyshould take in cancer. Activation or "hyping" of macrophages was thoughtto be important. However, in an examination by Romans and Falk ofperitoneal macrophages obtained from patients with neoplastic disease,there was definite evidence that these macrophages were alreadyactivated yet were co-existing with cancer cells and not causing theirdestruction.

In the early part of this year it has been shown by several independentinvestigators that the malfunction of macrophages or the putitive blockis due to excessive prostaglandin and that this can be altered in tissueculture by corticosteroids, ASA, and the non-steroidal anti-inflammatorydrugs, i.e. indomethacin, and naproxen (Naprosyn™). Again, in animaltumors it was repeatedly demonstrated that these substances could alterthe response to neoplastic cells and that various combinations of thesesubstances employed with immune enhancing agents could produce verycredible success in eliminating experimental tumors. Lala and co-workerscombined Indomethacin therapy with Interleukin 2 and showed that thiscould effect a cure with experiment neoplasm.

There were continued problems with the use of any of these agents in theactual human in vivo experience. All of the non-steroidalanti-inflammatory agents (NSAID) produced major toxicity in terms ofgastro-intestinal, neurological, and other areas. Thus, the basis of thepresent approach is that under general circumstances the use of theseagents in human disease, in sufficient amounts, the drug will penetrateto any pathological tissue to alter therapeutically local prostaglandinproduction. While intravenous preparations exist of Indomethacin and nowof other agents, the data is overwhelming, as is our own experience,that using these drugs alone produces prohibitive side effects in humansubjects. Therefore only insufficient amounts can be brought into thebody to effect more than occasional responses in neoplasm.

However the majority of the evidence is present to indicate andtherefore it can be postulated that the basis for neoplastic developmentand how the initial cell "sneaks by" the immune surveillance mechanismrelates to its production of prostaglandin. One need postulate only onemutation to alter the amount of prostaglandin synthesis produced bycells when they become "malignant" to establish a mechanism of blockingout the initial cell in any immune reaction, i.e. the macrophage. Ittherefore became essential to develop a combination of NSAIDS forclinical use to produce a major improvement in response in neoplasticdisease and other conditions where excessive prostaglandin synthesisrepresents the basis of the pathogenesis of this disease state, i.e.arthritis, and various others of the so-called connective tissueinflammatory disorders and/or auto-aggressive diseases.

See also:

1. Modulation of Immunity in Cancer Patients by ProstaglandinAntagonists, Immunity to Cancer II, Alan R. Liss, Inc.; and

2. Goodwin, J. S. (1981) Prostaglandin E and Cancer Growth Potential forImmunotherapy with Prostaglandin Synthesis Inhibitors, Augmentive Agentsin Cancer Therapy, Raven Press, New York.

U.S. Pat. No. 4,711,780 teaches a pharmaceutical composition comprisingVitamin C, a zinc salt, a sulfur amino acid for treating surfaceepithelium for epithelium regeneration. Hyaluronic acid may be added forapplications in the reproductive tract.

Japanese Patent Publication 63/045223 relates to the treatment ofdisease caused by retroviruses. Hyaluronic acid is taught for preventionor therapy of leukemia or AIDS by suppressing replication of the virus.

An article entitled "Inactivation of Herpes Simplex Viruses by NonionicSurfactants" by one of the inventors herein (Dr. Samuel Asculai) amongothers [published in Antimicrobial Agents and Chemotherapy, April 1978,pp.686-690] disclosed nonionic surface-active agents, for examplenonoxynol-9 found in Delfen™, "possessing ether or amide linkagesbetween the hydrophilic and hydrophobic portions of the molecule rapidlyinactivated the infectivity of herpes simplex viruses. The activitystemmed from the ability of nonionic surfactants to dissolvelipid-containing membranes. This was confirmed by observing surfactantdestruction of mammalian cell plasma membranes and herpes simplex virusenvelopes. Proprietary vaginal contraceptive formulations containingnonionic surfactants also inactivated herpes simplex virus infectivity.This observation suggests that nonionic surfactants in appropriateformulation could effectively prevent herpes simplex virustransmission."

SUMMARY OF THE INVENTION

Applicants have now discovered that combinations and formulations (forexample an injectable formulation) can be provided for administration toa mammal for the treatment of a disease or condition, which combinationsor formulations employ or incorporate as the case may be atherapeutically effective non-toxic amount of a medicinal and/ortherapeutic agent to treat the disease or condition (for example a freeradical scavenger (for example ascorbic acid (Vitamin C)), Vitamin C(for the treatment of mononucleosis), an anti-cancer agent,chemotherapeutic agent, anti-viral agents for example a nonionicsurfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found inDelfen™ contraceptive cream, and anionic surfactants (e.g. cetylpyridinium chloride) and cationic surfactants (e.g. benzalkoniumchloride), non-steroidal anti-inflammatory drugs (NSAID) for exampleindomethacin, naproxen and (+/-) tromethamine salt of ketorolac (soldunder the trademark Toradol™) and steroidal anti-inflammatory drugs,anti-fungal agent, detoxifying agents (for example for administrationrectally in an enema), analgesic, bronchodilator, anti-bacterial agent,antibiotics, drugs for the treatment of vascular ischemia (for examplediabetes and Berger's disease), anti-body monoclonal agent, minoxidilfor topical application for hair growth, diuretics (for examplefurosemide (sold under the trademark Lasix™)), immunosuppressants (forexample cyclosporins), lymphokynes (such as interleukin--2 and thelike), alpha-and-β-interferon and the like) administered with, orcarried in, an amount of hyaluronic acid and/or salts thereof (forexample the sodium salt) and/or homologues, analogues, derivatives,complexes, esters, fragments, and/or sub units of hyaluronic acid(preferably hyaluronic acid and salts thereof) sufficient to facilitatethe agent's penetration through the tissue (including scar tissue), atthe site to be treated through the cell membranes into the individualcells to be treated. When such combinations and formulations areadministered to patients suffering from the disease or condition, thedisease or condition is unexpectedly improved.

The formulation can be administered among other methods, intravenously,intra arterially, intraperitoneally, intrapleurally, transdermally, onthe skin (topically), rectally, orally or by direct injection (forexample into a tumor, into an abscess or similar disease focus) or puton a patch to be secured to the skin of the patient. The hyaluronic acidand/or salts thereof and the agent can be administered separately butare administered in sufficient amounts and in an immediate time sequenceor interval (preferably concurrently and more preferablysimultaneously), preferably at the identical site (e.g. one givenintravenously and the other "piggy backed"), to treat the disease orcondition.

Thus according to an aspect of the invention, a combination is providedsuitable for use to treat a condition or disease, the combinationcomprising therapeutically effective non toxic amounts of

(a) a medicinal and/or therapeutic agent to treat a disease or condition(for example a free radical scavenger (for example ascorbic acid(Vitamin C)), Vitamin C (for the treatment of mononucleosis), ananti-cancer agent, chemotherapeutic agent, anti-viral agents for examplea nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxyethanol] found in Delfen™ contraceptive cream, and anionic surfactants(e.g. cetyl pyridinium chloride) and cationic surfactants (e.g.benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID)for example indomethacin, naproxen and (+/-) tromethamine salt ofketorolac (sold under the trademark Toradol™) and steroidalanti-inflammatory drugs for example *), anti-fungal agent, detoxifyingagents (for example for administration rectally in an enema), analgesic,bronchodilator, anti-bacterial agent, antibiotics, drugs for thetreatment of vascular ischemia (for example diabetes and Berger'sdisease), anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics (for example furosemide (sold under thetrademark Lasix™)), immunosuppressants (for example cyclosporins) ,lymphokynes (such as interleukin--2 and the like),alpha-and-β-interferon and the like) and

(b) a sufficient amount of hyaluronic acid and/or salts thereof (forexample sodium salt) and/or homologues, analogues, derivatives,complexes, esters, fragments, and/or subunits of hyaluronic acid,preferably hyaluronic acid and salts thereof, sufficient to facilitatethe agent's penetration through the tissue (including scar tissue) atthe site to be treated through the cell membranes into the individualcells to be treated.

The combination can be administered separately or as a mixture orsolution. If administered separately the components are preferablyadministered simultaneously and at the identical site.

According to another aspect of the invention, a formulation is providedsuitable for use to treat a condition or disease, the formulationcomprising a therapeutically effective non-toxic amount of a medicinaland/or therapeutic agent to treat a disease or condition (for example afree radical scavenger (for example a free radical scavenger (forexample ascorbic acid (Vitamin C)), Vitamin C (for the treatment ofmononucleosis), an anti-cancer agent, chemotherapeutic agent, anti-viralagents for example a nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxypolyethoxy ethanol] found in Delfen™ contraceptive cream, and anionicsurfactants (e.g. cetyl pyridinium chloride) and cationic surfactants(e.g. benzalkonium chloride), non-steroidal anti-inflammatory drugs(NSAID) for example indomethacin, naproxen and (+/-) tromethamine saltof ketorolac (sold under the trademark Toradol™) and steroidalanti-inflammatory drugs, anti-fungal agent, detoxifying agents (forexample for administration rectally in an enema), analgesic,bronchodilator, anti-bacterial agent, antibiotics, drugs for thetreatment of vascular ischemia (for example diabetes and Berger'sdisease), anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics (for example furosemide (sold under thetrademark Lasix™)), immunosuppressants (for example cyclosporins),lymphmokynes (such as interleukin--2 and the like),alpha-and-β-interferon and the like), in an amount of hyaluronic acidand/or salts thereof (for example the sodium salt) and/or homologues,analogues, derivatives, complexes, esters, fragments and sub units ofhyaluronic acid, preferably hyaluronic acid and salts thereof,sufficient to facilitate the agent at the site to be treated, topenetrate through the tissue (including scar tissue) through cellmembranes into the individual cells to be treated.

According to another aspect of the invention a method of treating acondition or a disease in a mammal is provided comprising administeringto the mammal, a combination of a therapeutically effective non-toxicamount of

(a) a medicinal and/or therapeutic agent to treat a disease or condition(for example a free radical scavenger (for example ascorbic acid(Vitamin C)), Vitamin C (for the treatment of mononucleosis), ananti-cancer agent, chemotherapeutic agent, anti-viral agents for examplea nonionic surfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxyethanol] found in Delfen™ contraceptive cream, and anionic surfactants(e.g. cetyl pyridinium chloride) and cationic surfactants (e.g.benzalkonium chloride), non-steroidal anti-inflammatory drugs (NSAID)for example indomethacin, naproxen and (+/-) tromethamine salt ofketorolac (sold under the trademark Toradol™) and steroidalanti-inflammatory drugs, anti-fungal agent, detoxifying agents (forexample for administration rectally in an enemal), analgesic,bronchodilator, anti-bacterial agent, antibiotics, drugs for thetreatment of vascular ischemia (for example diabetes and Berger'sdisease), anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics (for example furosemide (sold under thetrademark Lasix™)), immunosuppressants (for example cyclosporins),lymphokynes (such as interleukin--2 and the like),alpha-and-β-interferon and the like) and

(b) a sufficient amount of hyaluronic acid and/or salts thereof (forexample sodium salt) and/or homologues, analogues, derivatives,complexes, esters, fragments, and/or sub units of hyaluronic acid,preferably hyaluronic acid and salts thereof sufficient to facilitatethe agent at the site to be treated to penetrate through the tissue(including scar tissue), through the cell membranes into the individualcells to be treated.

Preferably (a) and (b) are administered simultaneously at the identicalsite, for example, one intravenously and the other "piggy backed".

According to another aspect of the invention a method of treatingdisease or a condition is provided comprising administering to a mammala therapeutically effective non toxic amount of a formulation comprisinga therapeutically effective amount of a medicinal and/or therapeuticagent to treat a disease or condition (for example a vitamin (forexample a free radical scavenger (for example ascorbic acid (VitaminC)), Vitamin C (for the treatment of mononucleosis), an anti-canceragent, chemotherapeutic agent, anti-viral agents for example a nonionicsurfactant, e.g. nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found inDelfen™ contraceptive cream, and anionic surfactants (e.g. cetylpyridinium chloride) and cationic surfactants (e.g. benzalkoniumchloride), non-steroidal anti-inflammatory drugs (NSAID) for exampleindomethacin, naproxen and (+/-) tromethamine salt of ketorolac (soldunder the trademark Toradol™) and steroidal anti-inflammatory drugs,anti-fungal agent, detoxifying agents (for example for administrationrectally in an enema), analgesic, bronchodilator, anti-bacterial agent,antibiotics, drugs for the treatment of vascular ischemia (for examplediabetes and Berger's disease), anti-body monoclonal agent, minoxidilfor topical application for hair growth, diuretics (for examplefurosemide (sold under the trademark Lasix™)), immunosuppressants (forexample cyclosporins), lymphokynes (such as interleukin--2 and thelike), alpha-and-β-interferon and the like) in an amount of hyaluronicacid and/or salts thereof (for example the sodium salt) and/orhomologues, analogues, derivatives, complexes, esters, fragments and/orsub units of hyaluronic acid, preferably hyaluronic acid and saltsthereof, sufficient to facilitate the agent at the site to be treated topenetrate through the tissue (including scar tissue) through cellmembranes into the individual cells to be treated.

According to another aspect of the invention, delivery of atherapeutically effective amount of a medicinal and/or therapeutic agentto treat a disease or condition in a mammal is provided, the deliverycomprising administering a therapeutically effective non toxic amount ofa medicinal and/or therapeutic agent (for example a free radicalscavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for thetreatment of mononucleosis), an anti-cancer agent, chemotherapeuticagent, anti-viral agents for example a nonionic surfactant, e.g.nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in Delfen™contraceptive cream, and anionic surfactants (e.g. cetyl pyridiniumchloride) and cationic surfactants (e.g. benzalkonium chloride),non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin,naproxen and (+/-) tromethamine salt of ketorolac (sold under thetrademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungalagent, detoxifying agents (for example for administration rectally in anenema), analgesic, bronchodilator, anti-bacterial agent, antibiotics,drugs for the treatment of vascular ischemia (for example diabetes andBerger's disease), anti-body monoclonal agent, minoxidil for topicalapplication for hair growth, diuretics (for example furosemide (soldunder the trademark Lasix™)), immunosuppressants (for examplecyclosporins), lymphokynes (such as interleukin--2 and the like),alpha-and-β-interferon and the like) with a sufficient amount ofhyaluronic acid. and/or salts thereof and/or homologues, analogues,derivatives, complexes, esters, fragments, and sub units of hyaluronicacid, preferably hyaluronic acid and salts thereof, sufficient totransport or facilitate the transport of, the agent to the site to betreated through the cell membranes into the individual cells to betreated.

Thus according to another aspect of the invention, use of a combinationor formulation is provided to treat a disease or condition, thecombination and formulation comprising a therapeutically effectivenon-toxic amount of a medicinal and/or therapeutic agent to treat adisease or condition (for example a vitamin (for example a free radicalscavenger (for example ascorbic acid (Vitamin C)), Vitamin C (for thetreatment of mononucleosis), an anti-cancer agent, chemotherapeuticagent, anti-viral agents for example a nonionic surfactant, e.g.nonoxynol-9 [nonylphenoxy polyethoxy ethanol] found in Delfen™contraceptive cream, and anionic surfactants (e.g. cetyl pyridiniumchloride) and cationic surfactants (e.g. benzalkonium chloride),non-steroidal anti-inflammatory drugs (NSAID) for example indomethacin,naproxen and (+/-) tromethamine salt of ketorolac (sold under thetrademark Toradol™) and steroidal anti-inflammatory drugs, anti-fungalagent, detoxifying agents (for example for administration rectally in anenema), analgesic, bronchodilator, anti-bacterial agent, antibiotics,drugs for the treatment of vascular ischemia (for example diabetes andBerger's disease), anti-body monoclonal agent, minoxidil for topicalapplication for hair growth, diuretics (for example furosemide (soldunder the trademark Lasix™)), immunosuppressants (for examplecyclosporins), lymphokynes (such as interleukin--2 and the like),alpha-and-β-interferon and the like) and a sufficient amount ofhyaluronic acid and/or salts thereof (for example sodium salt) and/orhomologues, analogues, derivatives, complexes, esters, fragments, and/orsub units of hyaluronic acid, preferably hyaluronic acid and saltsthereof to facilitate agent transported to the site to be treated, topenetrate through the cell membranes into the individual cells to betreated.

Applicants postulate that the hyaluronic acid and/or salts thereofand/or the homologues, analogues, derivatives, complexes, esters,fragments, and/or sub units of hyaluronic acid facilitate the transportof the agent to the site to be treated and to penetrate the tissue(including scar tissue) through all membranes in the individual cells tobe treated.

By way of example and to illustrate the facilitation of the delivery ortransport of a chemical to a site in a mammal, when ethyl alcohol isinjected directly into a tumor, and sonographic (ultrasound) assessmentis made, it is not dispersed throughout the tumor. When the ethylalcohol to be administered into a tumor is carried by hyaluronic acidand/or salts thereof, sonographic assessment of the tumor, demonstratesthe dispersion of the ethyl alcohol throughout the tumor.

While Applicants postulate that the hyaluronic acid facilitates thetransport and delivery, Applicants' invention may be used as describedirrespective of the actual method of operation of the hyaluronic acidand/or salts thereof and/or the homologues, analogues, derivatives,complexes, esters, fragments and sub units of hyaluronic acid.

The combination of hyaluronic acid and salts thereof and other formswith different chemicals and drugs (Vitamin C, anti-cancer drugs, etc.)alters their distribution and performance in the human body and producesan unusual targeting for underperfused tissue and/or pathologicaltissue. In this regard the use of ascorbic acid (Vitamin C) as a freeradical scavenger (50 gm daily--1000 times the daily dose in therapeuticpurposes as a Vitamin) administered intravenously with 300-500 mg ofhyaluronic acid (sodium hyaluronate) immediately relieves bone pain andmuscle pain and reduces inflammation in cancer patients. The hyaluronicacid enhances the anti-neoplastic activity and effect of the ascorbicacid. It is thought that this enhanced activity eliminates the freeradicals by acting as a free radical scavenger. In any event thepatients feel better. This is also demonstrated with furosemide andhyaluronic acid where the activity of furosemide is enhanced onlyminimally when administered with hyaluronic acid to a "normal" subjectbut the activity is enhanced significantly when administered to apatient whose kidney is underperfused or malfunctioning due toinsufficient intra-vascular volume.

A similar situation occurs with the NSAIDS. As a major amount of solubleindomethacin is required, the chemical product was solubilized usingn-methyl glucamine at a dilution of 5 mg/ml of n-methyl glucamine (NMG).This substance is then passed through a 22 micron Milipore filter toproduce sterility. This material is non-toxic at 16 fold the therapeuticdose in animals and for this reason was considered appropriate to beused in human conditions. Thus, Indocid™ solubilized in NMG isadministered to human patients either into the tumor intraperitoneally,intrapleurally, or intravascularly at a varying dose up to 10 mg/kgwhere each dose of indomethacin is combined with 200-1000 mg ofhyaluronic acid (for example "LifeCore™"hyaluronic acid [sodiumhyaluronate]) diluted in the original solution of indomethacin and NMGwith for example the "LifeCore™" hyaluronic acid. This produces anappropriate mixture and can be administered safely by any of the routes.[Similar clinical studies have been done with hyaluronic acid preparedby other methods, i.e. extraction. The extracted material issatisfactory to use for intratumor, intraperitoneal or intrapleural usewith this substance.]

Thus and according to another aspect of the invention when an NSAID forexample indomethacin (dissolved in n-methyl glucamine) or other NSAID isadministered with greater than 200 mg hyaluronic acid for 1-2 mg/kg bodyweight of the NSAID (in one instance indomethacin and NMG), no majortoxic side effects occur such as gastro-intestinal distress,neurological abnormalities, depression, etc., even at elevated amountsof indomethacin (if necessary). If the amount of hyaluronic acid isdecreased below that amount, the usual side effects may begin toreoccur. In addition, the responses that have been observed are superiorwhen the NSAID (for example Indocid™) is combined with hyaluronic aciddemonstrating clearly that the combination is now "targeting" to thepathological tissue even when administered by the systemic intravenousroute. Thus, it has been observed that patients with neoplastic diseaseswhen receiving in addition to other chemicals (for example ascorbic acid[Vitamin C], phloretin and anti-cancer drugs), 50-200 mgNSAID--hyaluronic acid (sodium hyaluronate) (for example indomethacinand hyaluronic acid) experience dramatic relief of pain immediately.This is followed within a short period of time by a resolution andresorbtion of neoplastic lesions with an improvement of pulmonary, andliver function if there is tumor present in these organs. Thus the deadtumor material and the debris and tumor toxins appear to be bettereliminated by the body through the action of the macrophages whoseactivity is enhanced by the addition of the NSAID (or a steroidalanti-inflammatory drug) administered with hyaluronic acid (or salt orother form thereof). Thus Applicants believe that the addition of theNSAID for example with hyaluronic acid (sodium hyaluronate) deblocks themacrophages by preventing enzymatic production of prostaglandinsynthetase which blocks macrophage functioning. Thus the hyaluronic acid(and salt and other forms) not only enhance the activity of the NSAIDbut also reduce any side effects and toxicity that is associated withthe use of the prostaglandin synthesia inhibitors.

Examples of agents suitable for use as chemotherapeutic agents arenovantrone (Mitoxantrone), Methotrexate, 5-FU (5-Fluouracil),carboplatinum, methyl CCNU administered orally and Mitomycin C.

In one instance methotrexate has been administered with hyaluronic acidover an area of tumor tissue, (e.g. the chest wall) for a period of 5-7consecutive days. The patient's hemotological indices were lowered atleast comparable to methotrexate being given at the same doses eitherintravenously or orally. Further when the cancerous tumor breaks up(after treatment as previously described) in many instances the livercannot cope with the tumor toxins and debris and residue, killing thepatient. Not only is the use of hyaluronic acid with an NSAIDappropriate, so is the use of enemas employing hyaluronic acid (sodiumhyaluronate) and a detoxifying agent administered into the large bowel.

The hyaluronic acid and salts thereof may be utilized at varyingdoses--10 to 1000 mg/70 kg person with the optimal doses tending torange between 50 and 350 mg/70 kg individual. As there is no toxicity,the hyaluronic acid can obviously be administered in a dose excess (forexample 3000 mg/70 kg individual) without any adverse effects.

Thus, we have combined hyaluronic acid and/or salts thereof withcytotoxic chemotherapeutic agent, for example either administeringhyaluronic acid immediately after the agent (if the two cannot be mixedbeforehand) or having mixed the two, that is hyaluronic acid and thedrug, before administration. We have utilized for example, adriamycinadministering adriamycin prior to hyaluronic acid, methotrexate wherethe two agents are mixed together, mitomycin C, bleomycin,5-Fluorouracil, novantrone carbo- and cis-platinum, and in all of theselatter instances the drug has been mixed directly with hyaluronic acidat a dose of 10 mg/per ml of the hyaluronic acid increasing the totaldose up to 100 mg with the standard dose of the drug in question beingutilized.

Previously, we have utilized phloridzin, phloretin, and5-deoxyglucuronide of phloridzin as agents with dimethyl sulfoxide tocompetitively block glucose transport in neoplastic cells. These agentscan also be combined with hyaluronic acid at similar doses to thosealready mentioned for chemotherapeutic drugs where phloretin issolubilized for example by the agent N--methyl glucamine.

Thus, a treatment protocol in various different neoplastic situationsmay consist of the administration of Ascorbic Acid and Oncostatin IV, acombination of phloretin, solubilized in N methyl glucamine, with amixture of hyaluronic acid or salt thereof using a dose of 2 to 4 gramsof phloretin solubilized as described with 30 mg to 1000 mgs or more(dose excess) of hyaluronic acid or sodium salt. This has allowedsubstantially enhanced penetration of the drug into tumor cells and haseffected a much better result when these tumors are deprived of glucoseand then subsequently stressed either by hyperthermia, chemotherapyand/or radiation. Similarly, cytotoxic chemotherapeutic agents alreadymentioned have been combined with comparable doses of hyaluronic acidand and/or salts thereof administered either intravenously,intra-arterially, intraperitoneally or intrapleurally or directly intothe tumor by injection through a needle placed under sonographic or CTguidance.

Intradermal delivery of other drugs may also be accomplished withhyaluronic acid and/or salts thereof: for example insulin in diabetes,estrogen in post--menopausal women, progestegens in control of fertilityand anti-metabolites for the prevention of topical infection such asthose caused by coryne bacterium acnes. They may also be applied usinghyaluronic acid.

Intravenous administration of bronchodilators may also (for exampleaminophylline and theophylline) may also be accomplished with hyaluronicacid and/or salts thereof.

Enhancement of the effect of the bronchodilators by administration withhyaluronic acid has been the result. Oral administration with hyaluronicacid and/or salt may also be suitable.

According to another aspect of the invention, the combination of anon-ionic surfactant for example nonoxynol-9 [nonylphenoxy polyethoxyethanol] [found in Delfen (t.m.) contraceptive cream] and hyaluronicacid and/or salts thereof and other forms is provided for treating:

(a) herpes simplex type I and type II

(b) herpes zoster (shingles)

and unexpectedly provide immediate relief of symptoms and subsequentdisappearance of lesions.

The non-ionic surfactant preferably comprises an ether or an amidelinkage between the hydrophilic and hydrophobic portions of themolecule, being more active than the surfactants having an ester--or anether-- ester linkage.

The following nonionic surtactants and identified linkages are offeredfor consideration.

    ______________________________________                                        Surfactant                 Linkage                                            ______________________________________                                        None (control virus)                                                            5% Nonoxynol-9 (nonylphenoxy-polyethoxy ethanol) Ether                        1% Triton X-100 (p-diisobutylphenoxy-polyethoxy- Ether                        ethanol)                                                                      1% Brij-97 (polyoxyethylene (10) oleyl ether) Ether                           1% Span-20 (sorbitran monclamate) Ester                                       1% Span-80 (sorbitan moncoleate) Ester                                        1% Tween-20 (polysorbate 20) Ether-ester                                      1% Tween-80 (polysorbate 80) Ether-ester                                      1% Onyxol 345 Amide                                                         ______________________________________                                    

Where foreign objects (for example drainage tubes) must be implantedinto a human body and be left for use, it is imperative that the tissuesurrounding the implant not become infected because once the tissuebecomes infected, usually no matter how much antibiotic is administeredthe infection does not clear and the implant must be removed. Applicantshave found however that where the infected tissue surrounding theimplant is treated with the antibiotic carried in hyaluronic acid(sodium hyaluronate), the infection rapidly clears and the implant neednot be removed.

Applicants have also found that in respect of treating vascular ischemia(for example in cancer patients where the tumor tissue is underperfused, in patients suffering from diabetes and Berger's disease), theadministration of the medicines in hyaluronic acid (sodium hyaluronate)enhances the patient's response to the drug.

In patients suffering from brain tumors, the swelling must be reduced.Administration of dimethyl sulfoxide (DMSO) in amounts of less than 100gm daily in a 10% solution in hyaluronic acid (sodium hyaluronate)-300-500 mg reduces acute brain and spinal edema.

For the treatment of mononucleosis, Applicants have successfullyadministered to a patient suffering from a particularly bad case forsome time, Vitamin C and hyaluronic acid and the patient rapidlyrecovered.

One form of hyaluronic acid and/or salts thereof (for example sodiumsalt) and homologues, analogues, derivatives, complexes, esters,fragments, and sub units of hyaluronic acid, preferably hyaluronic acidand salts and thereof suitable for use with Applicant's invention is afraction supplied by Sterivet Laboratories Limited. One such fraction isa 15 ml vial of Sodium hyaluronate 20 mg/ml (300 mg/vial--Lot 2F3). Thesodium hyaluronate fraction is a 2% solution with a mean averagemolecular weight of about 225,000. The fraction also contains water q.s.which is triple distilled and sterile in accordance with the U.S.P. forinjection formulations. The vials of hyaluronic acid and/or saltsthereof may be carried in a Type 1 borosilicate glass vial closed by abutyl stopper which does not react with the contents of the vial.

The fraction of hyaluronic acid and/or salts thereof (for example sodiumsalt) and homologues, analogues, derivatives, complexes, esters,fragments, and sub units of hyaluronic acid, preferably hyaluronic acidand salts thereof may comprise hyaluronic acid and/or salts thereofhaving, the following characteristics:

a purified, substantially pyrogen-free fraction of hyaluronic acidobtained from a natural source having at least one characteristicselected from the group consisting of the following:

i) a molecular weight within the range of 150,000-225,000;

ii) less than about 1.25% sulphated mucopoly-saccharides on a totalweight basis;

iii) less than about 0.6% protein on a total weight basis;

iv) less than about 150 ppm iron on a total weight basis;

v) less than about 15 ppm lead on a total weight basis;

vi) less than 0.0025% glucosamine;

vii) less than 0.025% glucuronic acid;

viii) less than 0.025% N-acetylglucosamine;

ix) less than 0.0025% amino acids;

x) a UV extinction coefficient at 257 nm of less than about 0.275;

xi) a UV extinction coefficient at 280 nm of less than about 0.25; and

xii) a pH within the range of 7.3-7.9.

Preferably the hyaluronic acid is mixed with water and the fraction ofhyaluronic acid fraction has a mean average molecular weight within therange of 150,000-225,000. More preferably the fraction of hyaluronicacid comprises at least one characteristic selected from the groupconsisting of the following characteristics:

i) less than about 1% sulphated mucopolysaccharides on a total weightbasis;

ii) less than about 0.4% protein on a total weight basis;

iii) less than about 100 ppm iron on a total weight basis;

iv) less than about 10 ppm lead on a total weight basis;

v) less than 0.00166% glucosamine;

vi) less than 0.0166% glucuronic acid;

vii) less than 0.0166% N-acetylglucosamine;

viii) less than 0.00166% amino acids;

x) a UV extinction coefficient at 257 nm of less than about 0.23;

xi) a UV extinction coefficient at 280 nm of less than 0.19; and

xii) a pH within the range of 7.5-7.7

Other forms of hyaluronic acid and/or its salts, and homologues,derivatives, complexes, esters, fragments and sub units of hyaluronicacid may be chosen from other suppliers, for example those described inthe prior art documents previously referred to. In addition Applicantshave successfully employed sodium hyaluronate produced and supplied byLifeCore™ Biomedical, Inc. having the following specifications

    ______________________________________                                        Characteristics    Specification                                              ______________________________________                                          Appearance White to cream                                                      colored particles                                                            Odor No perceptible odor                                                      Viscosity Average <750,000 Daltons                                            Molecular Weight                                                              UV/Vis Scan, 190-820 nm Matches reference scan                                OD, 260 nm <0.25 OD units                                                     Hyaluronidase Sensitivity Positive response                                   IR Scan Matches reference                                                     pH, 10 mg/g solution 6.2-7.8                                                  Water 8% maximum                                                              Protein <0.3 mcg/mg NaHy                                                      Acetate <10.0 mcg/mg NaHy                                                     Heavy Metals, maximum ppm                                                   As     Cd     Cr     Co   Cu   Fe   Pb   Hg   Ni                                2.0 5.0 5.0 10.0 10.0 25.0 10.0 10.0 5.0                                    Microbial Bioburden                                                                              None observed                                                Endotoxin <0.07 EU/mg NaHy                                                    Biological Safety Testing Passes Rabbit Ocular                                 Toxicity Test                                                              ______________________________________                                    

The following references teach hyaluronic acid, sources thereof andprocesses of the manufacture and recovery thereof.

U.S. Pat. No. 4,141,973 teaches hyaluronic acid fractions (includingsodium salts) having:

"(a) an average molecular weight greater than about 750,000, preferablygreater than about 1,200,000--that is, a limiting viscosity numbergreater than about 1400 cm³ /g., and preferably greater than about 2000cm³ /g.;

(b) a protein content of less than 0.5% by weight;

(c) ultraviolet light absorbance of a 1% solution of sodium hyaluronateof less than 3.0 at 257 nanometers wavelength and less than 2.0 at 280nanometers wavelength;

(d) a kinematic viscosity of a 1% solution of sodium hyaluronate inphysiological buffer greater than about 1000 centistokes, preferablygreater than 10,000 centistokes;

(e) a molar optical rotation of a 0.1-0.2% sodium hyaluronate solutionin physiological buffer of less than -11×10³ degree--cm² /mole (ofdisaccharide) measured at 220 nanometers;

(f) no significant cellular infiltration of the vitreous and anteriorchamber, no flare in the aqueous humor, no haze or flare in the vitreousand no pathological changes to the cornea, lens, iris, retina, andchoroid of the owl monkey eye when one milliliter of a 1% solution ofsodium hyaluronate dissolved in physiological buffer is implanted in thevitreous replacing approximately one-half the existing liquid vitreous,said HUA being

(g) sterile and pyrogen free and

(h) non-antigenic."

Canadian Letters Patent 1,205,031 (which refers to U.S. Pat. No.4,141,973 as prior art) refers to hyaluronic acid fractions havingaverage molecular weights of from 50,000 to 100,000; 250,000 to350,000;and 500,000 to 730,000 and discusses processes of theirmanufacture.

Where high molecular weight hyaluronic acid (or salts or other formsthereof) is used, it must be diluted to permit administration and ensureno intramuscular coagulation.

One formulation of Ascorbic Acid (Vitamin C) injection USP ismanufactured by Steris Laboratories, Inc., Phoenix, Ariz., 85043 U.S.A.and comprises 22 mg/ml (equivalent to sodium ascorbate 250 mg/ml) in 30ml, 50 ml, or 100 ml individual containers, 30 ml size being preferred.

Thus Applicant has combined hyaluronic acid (and sodium hyaluronateand/or other forms) with medicinal and/or therapeutic agents for thetreatment of conditions and diseases with totally unexpected results:

For Example

    ______________________________________                                        Condition/Disease                                                                              Chemicals & Drugs                                            ______________________________________                                        1.   Cancer, increasing activity                                                                   free radical scavenger,                                     of macrophages superoxide dismutase,                                           ascorbic acid(Vitamin C)                                                      anti-cancer drugs, NSAID,                                                     Chemotherapeutic Agents,                                                      detoxifying Agents (e.g.                                                      cholestyramine)                                                             1A. Reduction of swelling Dimethyl Sulfoxide (DMSO)                            in brain of person                                                            suffering brain trauma                                                       2. Hair growth minoxidil - combination -                                        grow more hair when applied                                                   topically                                                                   3. Herpes, canker sore, nonionic surfactants, e.g.,                            shingles nonoxynol-9 and                                                       anionic, (e.g. cetyl                                                          pyridinium chloride) and                                                      cationic (e.g.                                                                benzalkonium choride),                                                        surfactants                                                                 4. Renal failure, cardiac diuretics - furosemide                               insufficiency, hypertension,                                                  edema                                                                        5. Infection, acne, antibiotics, antibacterials,                               mononucleosis antimicrobials, etc.,                                            ascorbic                                                                      acid and hyaluronic acid                                                    6. Transplants cyclosporins                                                   7. Inflammation, elimination non-steroidal anti-inflamma-                      of tumor break down mater- tories, NSAID e.g.                                 ial (toxins and debris), diclofenac,                                          decreasing side effects, indomethacin, piroxicam,                             relief of pain (e.g. ibuprofen, tromethamine salt                             back pain) of Ketorolac, naproxen,                                           8. Detoxification enema, detoxifying agent,                                     peritoneal dialysis                                                         9. Bronchodilation bronchodilators, e.g. beclo-                                 methasone diproprionate                                                       (sodium cromoglycate although                                                 not specifically a broncho-                                                   dialator), theophylline                                                     10. Vascular ischemia treat limbs in respect of                                 diabetes, Berger's disease,                                                   etc. with suitable medicine                                                   e.g. Trental                                                                11. HIV (AIDS) DMSO, Vitamin C, NSAID (e.g.                                     indomethacin, naproxen,                                                       ketorolac tromethamine),                                                      interferon, Vibramycin ™,                                                  (doxcycline), tetracycline                                                  12. Diabetes insulin                                                          13. Post-menopause estrogens replacement                                      14. Prevention of topical antimetabolites (e.g.                                infection sulfonamides)                                                      15. Reduction of swelling DMSO                                                16. Hypertension, cardiac Calcium channel blockers e.g. -                      insufficiency Nifedipine β-Blockers e.g.                                  atenolol, propranolol                                                       17. Prostaglandin acetylsalicylic acid                                         Synthesis inhilition                                                         18. Enhance oxygenation of perfusate                                           tissue by perfusion fluid                                                     bathing the tissue (for                                                       transplantation purposes                                                   ______________________________________                                    

In respect of the treatment of cancer particularly, Applicants have nowprovided a method of treatment and combinations of chemicals and drugswhich appear to enhance a patient's life expectancy and quality of life(even those patients not responding to the usual treatments). Applicantshave successfully treated patients with their invention, increasing therate of tumor destruction, improving for example macrophage function, toenable the body to eliminate the tumor cells, dead tumor waste, debris,and toxins.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1--1 is the comparison of abscess size with various formulations.

EXAMPLES

The following examples are offered to illustrate Applicants' invention.In substantially all, if not all cancer cases, the patient had beenunresponsive to conventional treatment. The hyaluronic acid referred toherein also includes other forms--for example sodium hyaluronate.

CASE I

A 59 year old male with a laryngeal epidermoid (squamous type tumor)treated in its primary state with a combination of surgery and radiationdeveloped metastatic disease in the liver some seven years later. Twomajor tumors were noted at a size of 12 cm and 6 cm diameter. These weretreated with combination therapy using systemic chemotherapy with addedDMSO to enhance penetration, phloretin

solubilized by N methyl glucamine with added DMSO to enhance penetrationand the direct administration of

adriamycin, carboplatinum and methotrexate into the tumor by systemicand intratumor injection therapy but in this case but with addedhyaluronic acid at a dose of 10 to 60 mgs for the different drugs. Thiswas achieved without any adverse effects and the patient was reassessedfour weeks later. At that point in time the smaller tumor haddisappeared entirely. The larger tumor was apparent only as a necroticfocus measuring now 5 cm in diameter but no apparent surviving tumorcould be detected by examination and needle biopsy. This caseillustrates the superior effect of hyaluronic acid on penetration ofdrug thus allowing better tumor destruction.

Follow-Up

Subsequently patient was given treatment of Indomethacin 300 mg and 300mg Hyaluronic Acid daily; patient was in remission, however patient diedof infection at a later date.

CASE II

A 42 year old female developed malignant melanoma with tumor present inthe left upper thigh and inguinal nodes, the abdominal cavity and liver,lungs, and the base of the brain affecting involvement of variouscranial nerves. Her primary tumor had been excised and she had developedrecurrent disease which was deemed untreatable as there is no cytotoxicor cytostatic chemotherapy that has major effects on this tumor when itis as widespread as observed in this patient. The patient was treatedwith a combination of phloretin solubilized in N methyl glucamine withadded hyaluronic acid at a dose of 10 to 50 mg/2 to 4 grams administeredintravenously and this agent was given for five days over 4-24hours/day. She also received hyperthermia to the various areas of thetumor and concomitant systemic therapy with carboplatinum with addedhyaluronic acid at a dose of 250 mg carboplatinum total plus methyl CCNUadministered at a total dose of 120 mg over 5 days orally while thepatient received hyaluronic acid systemically. Methotrexate mixed withhyaluronic acid was injected into the tumor which could be palpated inthe left thigh or inguinal region at a dose of 37.5 mg with 60 mg ofhyaluronic being added, the doses being divided equally at two differentdays by injection. The patient responded over the next 10 to 20 dayswith dramatic and total regression of the upper thigh and inguinaltumors, dramatic improvement in liver function with the tumors in theliver becoming cystic (generally regarded as a sign of tumor break down)and disappearance of the lung tumors. The tumor at the base of the brainregressed as manifested by improvement of her cranial nerve function anda decrease of pain and headaches. In this patient a tumor which isunresponsive to the majority of agents at this phase of development wasmade markedly responsive when the same agents were used with hyaluronicacid as a penetrating agent.

Follow-Up

The patient was subsequently given treatments of phloretin, indomethacin(NSAID) and hyaluronic acid. This patient is now in complete remission.

CASE III

A 55 year old female patient with cancer of the gallbladder occupyingthe entire right lobe of the liver. This patient had been treated onthree previous occasions with a combination of heat, systemicchemotherapy with added DMSO, phloretin with added DMSO and directinjection of cytotoxic drugs with added DMSO. Beginning May 1989 she wastreated with the comparable drugs with added hyaluronic acid as acarrier or dispersing molecule administered both systemically and bydirect injection into the tumor. The tumor which had shrunk marginallyby approximately 20% prior to this now reduced in size dramatically byover 50% and continues to diminish in size. This tumor is judgedunresponsive to these drugs alone when administered by the normalroutes.

Follow-Up

Unfortunately the patient relapsed, became depressed and died.

CASE IV

A 55 year old female with cancer of the colon metastatic to the liverwith one major large tumor mass occupying the entire right lobe of theliver and medial segment of the left lobe extending into the 1 left lobeand judged unresectable by a hepatic surgeon two months earlier wastreated with systemic chemotherapy and injection of chemotherapeuticagents directly into the tumor plus phloretin solubilized with N methylglucamine with hyaluronic acid and hyperthermia. The patient had a threeday course of therapy and was injected on one occasion directly into thetumor with cytotoxic drugs and hyaluronic acid and reassessed threeweeks later. Sonographic examination showed total liquafaction of thetumor leaving only a small rim of apparently viable tissue; 500 ccs ofamber colored fluid with necrotic tumor tissue present was drained fromthe now cystic lesion. This is an unusual and dramatic response for anadenocarcinoma which generally responds extremely slowly. It is judgedthat less than 30% of these patients achieved any significant diseaseregression utilizing standard cytotoxic or cytostatic chemotherapy. Theenhanced destruction here occurring over three weeks and is judged asdue to the use of the carrier penetrating molecule, hyaluronic acid.

Follow-Up

From the examinations, there was total tumor necrosis. The patienthowever died some time later of liver failure and pulmonary embolism.

CASE V

A 53 year old man with transitional cell cancer of the

bladder in a very advanced state of his disease with metastasesinvolving the entire left pelvis, extending to the periaortic andparapancreatic and supraclavicular nodes having recurred after previoussurgical excision, radiation and having not responded by majorregression to standard chemotherapy was treated using phloretinsolubilized in N-methyl glucamine with added hyaluronic acid with adirect injection of carboplatinum and methotrexate into the tumortissue. Hyperthermia to the areas of the tumor was also applied. Thepatient developed a dramatic response and developed a febrile reactiondue to tumor break down and release of bacteria. This reaction wascontrolled by antibiotics and appropriate hydration and as the patientwas observed through this phase a dramatic decrease in the size of thetumor was observed on an almost daily basis with an over 50% reductionin tumor size having occurred by 7 days after therapy. This is aremarkable and dramatic response of a tumor which at this phase had beenjudged as unresponsive to all therapy and it is thought to be due to theuse of the drug which blocks glucose transport employed here with acarrier and penetrating molecule, hyaluronic acid and chemotherapyadministered directly into the tumor with the same agent.

Follow-Up

There was, as a result, total tumor necrosis. However at a later date,the patient died of an infection.

CASE VI

This patient had a right upper lobe lesion diagnosed, confirmed bybiopsy and deemed not surgically resectable. This tumor, according todocumentation utilizing chemotherapy or radiotherapy has a zero responserate. He was treated with systemic chemotherapy in hyaluronic acid asfollows:

    ______________________________________                                        DATE         DRUG         DOSE                                                ______________________________________                                        05/10        vinblastine     3      mg                                          05/10 mitomycin 3 mg                                                          05/10 calcium leukovorin 40 mg                                                05/10 5fluorouracil 250 mg                                                    05/10 5fluorouracil 250 mg                                                    05/10 Oncostatin IV 3 mg                                                       Hyaluronic Acid III 10 mg                                                    05/11 carboplatin 250 mg                                                      05/11 vinblastine 5 mg                                                        05/11 mitomycin 4 mg                                                          05/11 calcium leukovorin 40 mg                                                05/11 5fluorouracil 250 mg                                                    05/11 5fluorouracil 250 mg                                                    05/12 carboplatin 100 mg                                                      05/12 vinblastine 2 mg                                                        05/12 5fluorouracil 250 mg                                                    05/12 5fluorouracil 250 mg                                                    05/12 calcium leukovorin 40 mg                                                05/12 Oncostatin IV 2 mg                                                       Hyaluronic Acid 20 mg                                                        06/19 mitomycin 5 mg                                                           Hyaluronic Acid 10 mg                                                        06/19 vinblastine 5 mg                                                         Hyaluronic Acid IV 10 mg                                                     06/19 5fluorouracil 250 mg                                                     Hyaluronic Acid IV 10 mg                                                     06/19 5fluorouracil 250 mg                                                     Hyaluronic Acid IV 10 mg                                                     06/19 calcium leukovorin 40 mg                                                06/19 Oncostatin IV 3 mg                                                       Hyaluronic Acid 50 mg                                                        06/20 5fluorouracil 250 mg                                                     Hyaluronic Acid IV 10 mg                                                     06/20 5fluorouracil 250 mg                                                     Hyaluronic Acid IV 10 mg                                                     06/20 calcium leukovorin 40 mg                                                06/20 mitomycin 5 mg                                                           Hyaluronic Acid IV 10 mg                                                     06/20 vinblastine 5 mg                                                         Hyaluronic Acid IV 10 mg                                                     06/20 Oncostatin IV 3 m                                                        Hyaluronic Acid IV 50 mg                                                     06/21 Carboplatin 20 mg                                                        Hyaluronic Acid IT 10 mg                                                     06/21 methotrexate 12.5 mg                                                    06/21 carboplatin 150 mg                                                       Hyaluronic Acid IV 50 mg                                                      Oncostatin IV 3 mg                                                            Hyaluronic Acid IV 50 mg                                                     06/22 carboplatin 100 mg                                                       Hyaluronic Acid IV 10 mg                                                     06/22 Oncostatin IV 3 g                                                        Hyaluronic Acid IV 50 mg                                                     06/23 Oncostatin IV 3 g                                                        Hyaluronic Acid IV 50 mg                                                     08/16 calcium leukovorin 40 mg                                                08/16 5fluorouracil 500 mg                                                     Hyaluronic Acid IV 50 mg                                                     08/16 carboplatin 250 mg                                                       Hyaluronic Acid IV 100 mg                                                     Oncostatin IV 3 g                                                             Hyaluronic Acid IV 100 mg                                                    08/17 carboplatin 200 mg                                                       Hyaluronic Acid IV 150 mg                                                    08/17 carboplatin 30 mg                                                        Hyaluronic Acid IV 50 mg                                                     08/17 adriamycin 2.5 mg                                                        Hyaluronic Acid 10 mg                                                         Oncostatin 3 g                                                                Hyaluronic Acid 100 mg                                                       08/18 5fluorouracil 500 mg                                                     Hyaluronic Acid 100 mg                                                       08/18 calcium leukovorin 40 mg                                                 Oncostatin IV 2 g                                                             Hyaluronic Acid 200 mg                                                     ______________________________________                                    

He was also treated with phloretin in hyaluronic acid. His tumor wasinjected with the following chemotherapeutic agents in hyaluronic acid:

    ______________________________________                                        DATE         DRUG       DOSE                                                  ______________________________________                                        05/11        methotrexate   12.5   mg                                            hyaluronic acid 50 mg                                                         adriamycin 1 mg                                                              06/21 methotrexate 12.5 mg                                                     carboplatin 20 mg                                                             hyaluronic acid 10 mg                                                        08/18 carboplatin 30 mg                                                        hyaluronic acid 50 mg                                                        08/18 adriamycin 25.5 mg                                                       hyaluronic acid 10 mg                                                      ______________________________________                                    

He has had regression of his disease by 50 per cent in a situation thatis otherwise not treatable. This therefore documents that unresponsivetumors can respond to chemotherapy when administered in hyaluronic acidand/or salts thereof.

CASE VII

Female patient, aged 58, had a massive cancer of the breast withsupraclavicular and auxiliary lymph nodes palpable. This has beenconfirmed by a biopsy. She was treated with combination systemic therapyand hyperthermia and did not improve significantly. She then receivedradiation from December, 1988 to January, 1989. She was subsequentlyseen again by Dr. Falk on May 17, 1989 and had not had a response totherapy to date. She then developed a plural effusion. She was treatedby Dr. Falk by a combination of chemotherapeutic agents as follows:

(Hyaluronic Acid may be Sodium Hyaluronate)

    ______________________________________                                        DATE         DRUG         DOSE                                                ______________________________________                                        05/16        methotrexate    25     mg                                           Hyaluronic Acid IT 10 mg                                                     05/16 methotrexate 25 mg                                                       Hyaluronic Acid 10 mg                                                         axilla IT                                                                    05/16 methotrexate 25 mg                                                       Hyaluronic Acid 10 mg                                                         SC node IT                                                                   05/16 Oncostatin IV 3 g                                                        Hyaluronic Acid 20 mg                                                        05/17 5fluorouracil 250 mg                                                    05/17 5fluorouracil 250 mg                                                    05/17 vinblastine 5 mg                                                        05/17 mitomycin 5 mg                                                          05/17 Oncostatin IV 3 mg                                                       Hyaluronic Acid 30 mg                                                        06/02 methotrexate 25 mg                                                       Hyaluronic Acid IT 30 mg                                                     06/02 vinblastine 5 mg                                                         Hyaluronic Acid IV 10 mg                                                     06/02 Oncostatin IV 3 g                                                        Hyaluronic Acid 30 mg                                                        06/05 5fluorouracil 250 mg                                                     Hyaluronic Acid IV 10 mg                                                     06/05 5fluorouracil 250 mg                                                     Hyaluronic Acid IV 10 mg                                                     06/05 calcium leukovorin 35 mg                                                06/05 vinblastine 5 mg                                                         Hyaluronic Acid IV 10 mg                                                     06/05 Oncostatin IV 3 g                                                        Hyaluronic Acid 30 mg                                                        06/21 carboplatin 20 mg                                                        Hyaluronic Acid IT 10 mg                                                     06/21 methotrexate 12.5 mg                                                    06/21 vinblastine 5 mg                                                         Hyaluronic Acid IV 10 mg                                                     06/21 mitomycin 5 mg                                                           Hyaluronic Acid IV 10 mg                                                     06/21 Oncostatin IV 3 mg                                                       Hyaluronic Acid 50 mg                                                        07/10 carboplatin 25 mg                                                        Hyaluronic Acid IT 20 mg                                                     07/10 methotrexate 12.5 mg                                                     Hyaluronic Acid IT 20 mg                                                     07/10 Oncostatin IV 3 g                                                        Hyaluronic Acid 50 mg                                                        07/12 Oncostatin IV 2 g                                                        Hyaluronic Acid 50 mg                                                        08/14 vinblastine 5 mg                                                         Hyaluronic Acid IV 50 mg                                                     08/14 5fluorouracil 50 mg                                                      Hyaluronic Acid IV 50 mg                                                     08/14 calcium leukovorin 30 mg                                                08/14 Oncostatin IV 3 g                                                        Hyaluronic Acid 100 mg                                                       08/16 Oncostatin IV 3 g                                                        Hyaluronic Acid 100 mg                                                     ______________________________________                                    

She had also had a thoracentesis with subsequent instillation of5fluorouracil, mitomycin C and hyaluronic acid into the chest cavity.Her pleural effusion is totally resolved. The lesions in her breastcontinue to recede and her supraclavicular and axillary lymph adenopathyis totally gone.

This patient represents a response with relatively low doses ofhyaluronic acid and/or salts thereof added to conventional chemotherapyused systemically by injection into the tumor and by intra-pleuralcavity instillation. The response has been further enhanced by the useof phloretin in synacid T.M. (hyaluronic acid and/or salts thereof) atthe same time.

Follow-Up

At a much later date this patient is in remission and doing very well.

CASE VIII

This is a 62 year old female treated previously with systemicchemotherapy, two different drug combinations without any response. Shewas referred for treatment including hyperthermia, and directchemotherapy injections to which she responded initially, beginningSeptember.

She was noted in April-May, to have an increase in the tumour in theright upper lobe of her lung. This tumour was an anaplastic small cellcarcinoma. The tumour was treated by injecting into the lesion bleomycinwith hyaluronic acid and indomethacin with hyaluronic acid. She alsoreceived systemically indomethacin 300 mg daily with 300 mg hyaluronicacid. The patient was followed radiologically and improved verydramatically over the next 2 to 4 weeks. The last film report shows thatthe left hemi-thorax is clear. On the right side there is no evidence ofpleural reaction. There is a prominent right upper lobe volume loss withelevation of the right hilum. The area of increased lucency in the rightapex may represent a region of cavitation within the collapsed lobe orelevation of the superior segment of the right lower lobe. Comparisonwith previous films shows that the mass has decreased significantly insize and cannot now be distinctly identified on this examination.

The applicants believe that this response is a direct result of thecarrier molecule--hyaluronic acid--injected with a chemotherapeuticagent and with a non-steriodal anti-inflammatory drug to assist inclearance of the necrotic tumour.

CASE IX

This patient was diagnosed as having a gastric cancer July, 1988 and itwas deemed unresectable. A gastroenterostomy-type of bypass wasperformed. Saw the patient initially in August and treatment wasinitiated in September, 1988. At that time he was heated and receivedphloretin with very low dose chemotherapy employing 5-FU plus immuneaugmenting agents.

This therapy essentially awash continued until February, 1989 when Dr.Falk began to use DMSO as a carrier/penetrating agent in addition toMSN. He did receive increasing amounts of chemotherapy employing 5 FUleukovorin, mitomycin C and methotrexate and subsequently in July andearly August, as there was tumor progression, he also receivednovantrone.

As of May he began to receive these drugs in hyaluronic acid but theinitial amounts of hyaluronic acid were small, employing 10-30 mg peraverage dose with the original drug i.e. phloretin, or thechemotherapeutic agent. There was some initial improvement in his statusbut then in mid August he progressed to a situation where there wasincreasing evidence of gastric obstruction, and also obstruction of thebiliary tree with jaundice and elevation of the bilirubin. Dr. Falk thentreated with higher doses of hyaluronic acid to a total dose of 500-600mg of hyaluronic acid divided among the different drugs. The patientcontinued to receive the same types of drugs.

While his condition initially deteriorated, an upper gastro-intestinalseries performed on September the 7th shows his gastric bypass to betotally open whereas prior to this the patient had been vomiting alloral intake. His status has now steadily improved.

On the basis that the patient received identical drugs earlier, theimprovement must be attributed to the higher doses of the carriermolecule, allowing for better penetration of drug into what is always ascarred, fibrotic tumor and generally fatal at this stage.

Follow-Up

Unfortunately at a subsequent date, patient died as a consequence oftumor necrosis and scar tissue developing--not from cancer.

CASE X

Patient was diagnosed as having a hepatoma now over 2 years age. Thetumor had been stable or with minimal growth over the past 18 months.Since treatment with low dose chemotherapy and the carrier/penetratingmolecule, hyaluronic acid, she appears to have had a complete response.Her alkaline phosphatase is now at 150 international units and theremainder of her liver function tests are essentially normal. Herultrasound show no distinct tumors anymore in the liver. Dr. Falk is nowtreating her once every 2-3 months.

Follow-Up

This patient is still doing well.

CASE XI

This patient was infused on Jun. 15, 1989 with chemotherapy with addedhyaluronic acid on one occasion. She then received hyperthermia.Previously with multiple hepatic metastases from cancer of the breastshe had been stable on tamoxifen, the estrogen-blocking substance.

After one course of infusion of only 8 hours she has had what wouldappear to be a complete response. Her ultrasound now shows no tumorpresent in the liver and her liver function tests are all normal.

For the present no further treatment necessary are following her andcontinuing her on tamoxifen to block the estrogen receptor.

Follow-Up

This patient relapsed after another doctor gave vaginal estrogen cream(tamoxifen) to her for vaginal irritation. In response, patient wasgiven treatments of 300 mg of indomethacin in 300 mg of hyaluronic aciddaily. She is now in remission.

CASE XIA

This patient had a massive leomyosarcoma of the uterus resected on Mar.26, 1989. There was residual tumor present as demonstrated by a CATscan. Dr. Falk has treated her with a combination of hyperthermia, verylow dose methotrexate using this intraperitonealy with acarrier/penetrating molecule--hyaluronic said and then using the agentthat blocks glucase transport protein--phloretin, also with hyaluronicacid and alpha II interferon intraperitonealy again combined withhyaluronic acid.

On sequential CT scan this patient shows significant improvement in sizeof the residual mass. As soft tissue sarcomas are so very resistant toall forms of therapy this could be described as an unusual response andis in all likelihood related to the use of the carrier/penetratingmolecule--hyaluronic acid. Dr. Falk is now treating this patientapproximately every 6-8 weeks for 2 days and hopefully her regression oftumor will continue. If that is the case, than one could considerclosing her colostomy in about 6 month's time.

Follow-Up

Some tumor grew back. Patient was given treatments of Vitamin C (50 mgdaily), indomethacin (300 mg daily) in 300 mg of hyaluronic acid. Thispatient is feeling much better.

CASE XIB

This patient has received relatively low doses initially of methyl CCNUand carboplatin with methotrexate injected into the inguinal recurrentmelanoma. All of these molecules were given in the carrier/penetratingagent hyaluronic acid. In addition she received the agent that blocksglucose transport which Dr. Falk has developed. This is a moleculecalled phloretin which was used many years ago. It has been solubilizedin a special solution and is also given with hyaluronic acid as it willalso enhance the penetration of this molecule into the tumor. Dr. Falkthen treated her with hyperthermia using both capacitive and inductiveradio frequency hyperthermia and microwave hyperthermia. In addition shehas received immune stimulating agents which Dr. Falk believes willproduce benefit but only in conjunction with other agents.

In the last 2 courses of treatment she has received only carboplatinwith added hyaluronic acid, phloretin with added hyaluronic acid andmethotrexate administered now by intra-peritoneal route at a lowdose--25-35 mg in hyaluronic acid again.

Dr. Falk saw her this week and he will treat her for 2 days. She isclinically in excellent condition. She has the one complaint ofright-sided back pain. On examination one does have the impression thatthis could be tenderness over the right kidney. The ultrasounds of herkidneys have suggested a solid mass in the right kidney which wasinterpreted as being either a hamartoma or even an angiomyolipoma.

In view of the patient's rather dramatic response Dr. Falk thinks itwould be worth while to get a CAT scan done of the abdomen. There isstill the question of a small cystic lesion in the right lobe of theliver but her liver function in now normal.

Follow-Up

This patient is now in complete remission.

CASE XII

The patient had an arterial line and subcutaneous port installed at thetime of the original abdominal surgery. He came to see Dr. Falk and itwas noted that there was redness, in duration and swelling around thesubcutaneous port. The patient had a febrile response and elevation ofhis leukocytes.

A .English Pound. 14 gauge plastic cannula was inserted into the areaand 75 cc of purulent material was drained and cultured growing E. coliand Pseudomonas aeruginosa. Dr. Falk treated him by irrigating the sitewith a combination of hyaluronic acid with ampicillin, hyaluronic acidwith flagyl., and hyaluronic acid with keflosporin. Thus the wound wasirrigated on a daily basis with 1 gram of ampicillin with 50 mgs. ofhyaluronic acid, 500 mgs. flagyl with 50 mgs. of hyaluronic acid and 1gram of Ancef with hyaluronic acid. During the first 2-3 days irrigationit was possible to continue to aspirate purulent material from thesubcutaneous site. Within 5 days there was no purulent materialremaining and there was just fluid present and by the end of the weekthere was no residual infection present. The port-a-cath continued tofunction over the next three months of the patient life.

This is cited as an example of anti-bacterial agents with addedhyaluronic acid producing better penetration of the various differentanti-bacterial drugs into the site of infection and one would have topostulate that there was improved penetration into the bacteriathemselves.

CASE XIII

This patient was operated on Jun. 1st, 1989 and a resection wasperformed of a portion rectum and sigmoid colon, and the smallintestine. Post-operatively on day 7 he was noted to have swelling andinduration in the wound tissue and two sites of purulent material weredrained. He was treated subsequently with local irrigation withampicillin 1 gram combined with 50 mgs. hyaluronic acid and 500 mgs. offlagyl combined with hyaluronic acid. These two areas of infectioncleared of any bacterial contamination within 4 days. The usual timerequired would be in the order of a number of weeks.

CASE XIV

This patient with cancer of the breast has an infected Hickman Line.This is an indwelling plastic catheter in the subclavian vein. Thisinfection was present subcutaneously with purulent material coming fromthe site of the entry of the plastic cannula. In this situation Dr. Falkinjected ampicillin 1 gram and 50 mgs. of hyaluronic acid directlyadjacent to the plastic catheter. In addition the patient receivedflagyl intravenously with added hyaluronic acid. The infection clearedand the catheter was presented in a matter of 4 days.

CASE XV

This man developed an abscess on the right upper quadrant of hisabdomen, in the anterior abdominal wall. This was drained in hospitalbut continued to be a problem. Dr. Falk has now discharged him and begunto irrigate this with ampicillin 500 mg daily and 200 mg of hyaluronicacid. While this abscess was drained and therefore should have recoveredeventually, it had taken a longer period of time than one would haveanticipated. The abscess grew both staphlyococcus aureus and e. coli.

After 2 days of irrigation with ampicillin and hyaluronic acid asdescribed, the cavity was clean, free of infection and beginning togranulate over nicely. Dr. Falk continued to treat him during the weekand it healed satisfactorily.

In other patients alpha 2- interferon was combined with hyaluronic acidand applied to a patients canker sores and the sores rapidly cleared up.

In another patient, methotrexate was carried in hyaluronic acid andapplied topically to a patient with psoriasis. The formulation wasabsorbed and the psoriasis cleared.

In ten other patients suffering from herpes simplex type I and II, theapplication of an effective amount of nonoxynol-9 [nonylphenoxypolyethoxy ethanol] (Delfen™) combined with hyaluronic acid and/or saltsthereof to the effected areas 2 to 3 times daily gave immediate reliefof the symptoms (pain) and disappearance of the lesions.

In at least two patients, an effective amount of nonoxynol-9 fortreating herpes zoster (shingles) was combined with hyaluronic acidand/or salts thereof and was successfully employed to treat the herpeszoster (shingles).

CASE XVI

A dentist with melanoma, age 51, developed acute herpes zoster in the9th thorasic dermital on the left side of his body. He was inexcruciating pain, not relieved by classical medications. Dr. Falk askedhim to take orally cyclofur as an antiviral but he did not begin thisimmediately. However, Dr. Falk also indicated that he should take"Delfen™" and "LifeCore™" hyaluronic acid, mix equal portions and thenapply this topically. He did this and had immediate relief of painwithin 5 minutes. The pain has remained absent for the next 4 days. Inaddition, the lesions of herpes zoster immediately began to disappearwithin the first 24 hours and now, 5 days later, none are apparent. Thisis a dramatic response suggesting a major antiviral affect of thiscombination, with the hyaluronic acid obviously enhancing penetration.

CASE XVII

This man developed stomach cancer which metastasized to his liver. Hewas treated for seven months with low dose chemotherapy (5 FU), lowdoses of mitomycin and novantrone with various amounts of hyaluronicacid, and Vitamin C (50 gm daily). There was no detectable tumor. He isnow in remission and all tumors are calcified.

CASE XVIII

This male patient had a serious car accident, shortly thereafter hedeveloped colon cancer which was resected with multiple livermetastases. He came to Dr. Falk in June, 1989. He was treated withchemotherapy (phloretin) and hyaluronic acid with heat. He remainedstable for approximately one year, then his alkaline phosphatase began"creeping up". Consequently, Dr. Falk treated him with Vitamin C (50 gmdaily for three days), hyaluronic acid (up to 300 mg daily),indomethacin in N-methyl glucamine (300 mg daily in the 300 mg ofhyaluronic acid), and Toradol™ (60 mg) once or twice daily withhyaluronic acid (50 mg) Since that time he has shown improvement. Hisalkaline phosphatase decreased, and therefore his liver is functioningbetter.

CASE XIX

This man, age 46, was diagnosed in the last three months with adifficult to treat broncheolar alveolar carcinoma of the lung.Appropriately, neither chemotherapy nor major amounts of radiation wereused, although spot radiation was given to two areas; one on either sideof the chest where there apparently was some indication of skeletalinvolvement.

Subsequent to that, the patient visited a cardio-pulmonary transplantunit in London who thought that a transplant might be appropriate butthere was a waiting list of about one year.

After this the patient went to Dr. Frederick Douwe's clinic in Germanyand was placed on a variety of regimens, the main direction of whichincludes; (a) immune enhancement at the T-cell level; and (b) freeradical scavenging and detoxification.

He has improved somewhat since this treatment was initiated withepisodes when he is very short of breath, having had one of those 24hours ago.

On examination, he has very severely diminished air entry on both sideswith bilateral rales and ronchi. There is no evidence of supraclavicularadenopathy. There is no evidence of skeletal tenderness at this point orof hepatic enlargement.

He then came to Dr. Falk and he treated him with Vitamin C (50 gms),non-steroidal indomethacin (NSAID) (100 mg--reduced from initial amountof 300 mg because of heartburn) dissolved in hyaluronic acid (300 mg).He improved dramatically after the first 5 days of therapy withreference to lung capacity and radialogical appearance on the X-ray.

Dr. Falk then prescribed daily injections of hyaluronic acid (300 mg)with Toradol™ (60 mg) to be taken at home ("home" being outside ofCanada).

Comparison has been made to the previous examination. Since thatprevious examination, there has been resolution of some of the increasedinterstitial markings so that the lungs now look clearer than they didon the previous exam. Nonetheless, increased interstitial markings arestill present within both lung fields.

CASE XX

A female patient, age 74, was diagnosed with cancer of the colon and wasresected. The cancer had however mastastasized to the liver (rightlobe). Over a one month period, she was treated twice with methotrexate(25 mg) in hyaluronic acid (400 mg) intraperitoneally, five times withoncostatin (2 gm) in hyaluronic acid (300-500 mg), Vitamin C (50 gm) inhyaluronic acid (300 mg), and indomethacin (NSAID) given twice, 100 mgof indomethacin in 300 mg hyaluronic acid and 250 mg of indomethacin in500 mg of hyaluronic acid.

The patient is now doing very well, feeling better, and the liver tumoris regressing (shrinking).

CASE XXI

This female patient, age 51, was diagnosed with cancer of the uteruswhich had spread to the lungs (leiomyosarcoma). Dr. Falk treated herwith various doses of oncostatin (low doses of 0.5 gm to 3 gm) withhyaluronic acid (300-500 mg), Vitamin C, (50 gm) in hyaluronic acid (300mg), and indomethacin in hyaluronic acid (intraperitoneally andintravenously).

The pelvic mass is presently regressing and the lungs are now stable.

CASE XXII

This man, age 52, has a history of Crohn's Disease and chronic infectionin the bowel from Crone's disease. He eventually developed a tumor inthe peritoneum (adenocarcinoma). The patient was treated with doses of 2gm and 3 gm of Oncostatin™ (phloretin) each in hyaluronic acid (500 mg)and DMSO (total of 2000). Doses of indomethacin ranging from 75 mg to450 mg in 200 to 700 mg of hyaluronic acid were given. Patient was alsotreated with Vitamin C (50 gm) in hyaluronic acid (300 mg), and naproxen(1 gm) in hyaluronic acid (400 mg). These treatments were given to thepatient via several routes intraperitoneally, intravenously, rectally(for detoxification) (insertion of catheter and administered rectally).The pain is now gone.

Patient was given CT Scan of the abdomen and pelvis. There is moderatehepatic steatosis without evidence of metastatic disease. The spleen,pancreas, adrenals and right kidney appear normal. There is a leftnephrostomy tube in place with no evidence of residual hydronephrosis.There is a large and necrotic tumor mass occupying most of the deeppelvis with anterior displacement of the urinary bladder and likely someinvasion of the prostate gland. There is no evidence of sacraldestruction although the rectal tumor is closely apposed to its anteriorsurface.

Thus there appears to be a large and necrotic pelvic tumor mass withoutevidence of sacral destruction, para-aortic lymphadenopathy or distalvisceral metastases. A left percutaneous transrenal ureteral stent is inplace.

The patient was seen Aug. 1, 1990, in the clinic and he has been feelingvery well. He is doing extremely well; the necrotic tumor mass is slowlyreducing in size.

CASE XXIII

This female patient, age 47, was diagnosed in January, 1990. A gastricresection and colonic replacement of oesophagus (for swallowing) wasperformed. She had also developed an intraperitoneal tumor. She wasgiven chemotherapy and lost her hair. (Dr. Falk gave her minoxidil andhyaluronic acid to apply to her scalp and her hair grew back). Dr. Falksaw this patient on Jun. 6, 1990, and gave her lower doses of phloretintogether with heat and hyaluronic acid, indomethacin in hyaluronic acid,and Vitamin C in hyaluronic acid.

Since the time of treatment, the patient has made good improvement. Shehas gained weight, and is no longer feeling any pain. Thecarcinoembryonic antigen is down to 26 nonograms/ml and steadilyfalling.

CASE XXIV

This man (age 45) first seen by Dr. Falk on Mar. 1, 1988, he wasdiagnosed with carcinoma of the pancreas. He was treated with DMSO andheat together with low doses of chemotherapy. Dr. Falk injected the DMSOand the other drugs into the tumor. More than one year later, thispatient was given treatments with Vitamin C, and other agents inhyaluronic acid. This patient is now in complete remission. He has notbeen treated in more than six months.

CASE XXV

Dr. Falk saw this female patient (age 62) in August, 1989. This womanwas diagnosed with carcinoma of the pancreas. She was treated with lowdoses of chemotherapy (5-FU and mitomycin) together with 300 mg ofhyaluronic acid and heat. She was having trouble with her bile ducts.She was operated on, but a tumor was not found and the bile ducts werebypassed. The patient was then treated with indomethacin and Vitamin Cin hyaluronic acid, and the heating treatments were stopped. Since hertreatment she has experienced a gain in weight and there is no evidenceof a significant tumor.

CASE XXVI

This female (age 18) patient was treated for infectious mononucleosis.Three months of testing the patient resulted in positive heterophileantibody tests. Patient had no energy. The patient was given 50 gm ofVitamin C and 300 mg of hyaluronic acid. Within sixteen hours of thetreatment her energy increased dramatically and within two weeks theheterophile antibody test became negative.

CASE XXVII

This woman (age 65) patient illustrates important points. Her previouschemotherapists did not recognize they had killed most of her tumor. Shehad been taking chemotherapy previously. However as the tumor wasbreaking up, as Dr. Falk has now concluded, there was a retention ofwater fluid in the area of the tumor (they should have looked at theultrasound for assistance). Dr. Falk saw her and treated her with heat,phloretin, Vitamin C, indomethacin and some 5-FU, all in hyaluronicacid. (According to her previous doctors, she had an enlarged tumorafter taking 5-FU. Therefore, they stopped chemotherapy). The patient isnow looking better and feeling better and there is no edema.

CASE XXVIII

This female patient had carcinoma of the ovary with intermittent tocomplete bowel obstruction with encasement of the bowel with tumor andalso significant amounts of pleural fluid. The most striking example ofthe effect of Lasix (furosemide) occurred under the followingcircumstances. On Apr. 28th and 29th, 1990, the patient excreted a totalvolume of 2,450 ml of urine over 48 hours despite the administration of0.33 per cent sodium chloride solution with added potassium chloride at40 mEq/l administered at the rate of 100-125 ml per hour. The patient'sbody weight was 40 kg. During this period of time the patient received120-200 mg of Lasix administered intravenously.

On Apr. 30th, she received 40 mg of Lasix with added 350 mg ofhyaluronic acid administered over half of an hour. She produced adiuresis within the following 5 hours of 2,500 ml of urine. During theevening hours with no additional Lasix being given, urine output felldramatically and she excreted only 400 ml of urine from 7:00 p.m. Apr.30th to 7:00 a.m. May 1st. At 7:30 a.m. she received 40 mg of Lasix in300 mg of hyaluronic acid administered intravenously. Over the next 8hours, this patient produced 2,600 ml of urine. This case demonstratesthe fact that even a relative insensitivity to furosemide (Lasix) can beovercome with the addition of hyaluronic acid to enhance drugpenetration to the appropriate area.

The similar type of phenomena has been observed by us in patients wherethere is a so called "hepatorenal syndrome" and where the kidney stopsexcreting urine due to the failure of the liver to function adequately.Under these circumstances, urine output may decrease to essentially zerolevels. This can be dramatically effected by furosemide (Lasix™)administered intravenously in hyaluronic acid, even though furosemide(Lasix™) administered by itself produced no effect.

CASE XXIX

In normal healthy individuals, it was observed that adding hyaluronicacid to furosemide (Lasix™) administered at a dose of 20 mgintravenously with 300 mg of hyaluronic acid, there was an increase ofurine excretion by 3 to 5 fold as compared to that observed withfurosemide (Lasix™) alone. This is cited as evidence that hyaluronicacid increases penetration/permeation of the drug and thus facilitatesits function.

CASE XXX

This balding patient applied minoxidil (Rogaine) topically to his scalp.There was minimal or little hair growth. Subsequently, the minoxidil wasapplied together with hyaluronic acid continuously every 2 to 3 days. Asa result this patient's hair has grown fuller and more rapidly.

CASE XXXI

This female patient (age 32) was diagnosed as having an epitheloidsarcoma on the basis of a Mayo Clinic review.

Her history of the disease dates back to Dec. 12, 1978, when shedeveloped nodularity in the left ring finger which was excised. She hashad recurrent episodes of this type of problem since then and has had anamputation of the left 4th finger. She has been extensively staged andinvestigated as she was found to have nodules of the same type ofdisease up her arm and a left axillary lymph node biopsy was positive inMarch, 1990 for an epitheloid sarcoma.

At the Mayo Clinic she received three courses of chemotherapy withmitomycin C, adriamycin, cisplatinum in high doses without any response.She was scheduled for a fore-quarter amputation for the sarcoma of theleft arm and forearm.

This patient was first seen by Dr. Falk on Jun. 25, 1990, and wastreated for three days with heat, phloretin-hyaluronic acid, vitaminC-hyaluronic acid, methotrexate-hyaluronic acid, and also receivedsolu-medrol. She did not have a clear response at that point in time andthe lesions remained the same.

She returned on Jul. 23 and was treated for three consecutive days witha reduced dose of phloretin, same dose of vitamin C-hyaluronic acid andreceived both naproxen and indomethacin with hyaluronic acid bothsubcutaneously and intravenously. She returned home and receivedToredol™ (Syntex--non-steroidal anti-inflammatory drug) intra-muscularlyon a daily basis at a dose of 30-120 mg administered once or twice perday with 100 mg of Hyal Pharmaceutical type hyaluronic acid.

She was reassessed on Aug. 20 and has had a dramatic decrease in size ofall measurable disease by greater than 50%. In fact, at this point,biopsy would have to be done to ascertain if there is any viable tumorpresent. The treatment plan is to continue on the Toredol™ andhyaluronic acid.

While the patient had some minimum response with heat, phloretin,conventional chemotherapy with the addition of hyaluronic acid withthese drugs, she did have an excellent response with the non-steroidalanti-inflammatory drugs using all three types; Indocid™, naproxen andToredol™ when combined with hyaluronic acid as a carrier/penetratingvehicle to facilitate targeting to pathological tissue. She has had fewif any of the standard side-effects that occur with the non-steroidalanti-inflammatory drugs.

CASE XXXII

This male was diagnosed as having gastric cancer in 1988. The tumor wasin the distal third of the oesophagus at the gastro-oesopageal junction.A Celestine tube was placed by an intraoperative abdominal procedure andsutured to the lesser curvature of the stomach.

The patient was treated from January, 1990 up until 3 months ago (June,1990). Repeated CAT scans have shown no change in any situation;symptomatically he had been completely well. Most recent CAT scan wasJun. 26, 1990. This raised questions in respect of some areas in theliver; however, sonographic examination suggested that these were infact homogenous.

On Jul. 4th he had some "hot dogs" a picnic. During the night he woke upwith acute left upper quadrant pain which was not associated with nauseaor vomiting. Subsequent to this he had episodes of pain essentiallyevery time he consumed any food. The pain was always the same, felt inthe back and the front of the abdomen and tended to "spread" to bothflanks. It has never been associated with any direct peritonealtenderness, vomiting, diarrhea or fever and chills. Investigationincluded the previous CAT scan done just eight days prior to the onsetof this pain, and an upper GI series with follow-through. Further CATscan now could not be done because he was still full of barium.

It is important to recognize that a significant dose of Demerol justbarely relieved his pain. Further examination is unremarkable. Therewere no abdominal, thoracic or lymph node findings to suggest any spreadof the disease.

Dr. Falk reviewed the X-rays with a Professor at the Department ofRadiology, Toronto General Hospital, University of Toronto. He suggestedthat the upper GI series was a classical picture of "tethering" of thesmall bowel. He said, this could be either from fibrous adhesions orfrom neoplastic disease, or indeed, a combination of both, as is verycommon with adenocarcinoma of the stomach. However, the neoplastic,seedings would necessarily be very minimal, as nothing shows on theprevious CAT scan.

Dr. Falk treated the patient with a combination of non-steroidalanti-inflammatories administered intravenously with hyaluronic acid inconjunction with hyperthermia and oncostatin, which is a combination ofphloretin and hyaluronic acid and achieved almost immediate relief ofpain. He can now eat without having symptoms (had lobster soup recentlyat one of the local restaurants).

Dr. Falk has also given him a supply of probanthine which he could use,as the type of pain that occurs with these type of adhesions is usuallyrelieved by one of the anti-cholinergic drugs. Dr. Falk has alsosuggested to him to come back for further therapy and continue when hegoes home on a combination of felden 10 mg b.i.d. and naprosyn 500 mgdirectly as suppository once per day and take zantac 150 mg twice a day.

In addition Dr. Falk placed him on Vibramycin (Doxycyline) 200 mg forone day and a 100 mg daily dosage for fourteen days. This is anantibacterial agent and also blocks intracellular and anerobicglycolosis.

Follow-Up

Recent biopsies showed chronic inflammation of the lower one third ofthe oesophagus (tube in oesophagus recently removed); however, therewere no malignancies found.

CASE XXXIII

This man has had major tumor breakdown and this has occurred only afterchemotherapy was omitted from the treatment regimen. This initially madehim significantly more ill; this was reflected only to a minor extent interms of his hepatic function tests. The alkaline phosphatase did becomeelevated. He had profound malaise, weakness, excessive fatigue and lossof appetite. This has been corrected by intensive use of indomethacin inhyaluronic acid and detoxification programs.

He was reassessed and was significantly better. Under ultrasound, thetumor shows virtually total necrosis. There is now increased normalliver tissue present.

CASE XXXIV

This man had a chronic abscess cavity in his pelvis with a bowelobstruction which necessitated an operation on Jan. 5, 1990. At thattime the cavity was irrigated out and drained through the perineum. Hehad an uneventful post-operative course and was discharged from hospitalon Jan. 18, 1990.

However, subsequently he developed a fever and because this had been alarge cavity in the pelvis, it now drained through the lower anteriorpart of his abdominal incision. This occurred two weeks prior to thepresent visit.

Dr. Falk assessed him. This is a large cavity and he thought that thiswould take 4 to 6 weeks to close. Dr. Falk, instituted daily irrigationsduring 5 day working week with ampicillin, flagyl and hyaluronic acidusing 500 mg of ampicillin and 500 mg of flagyl. This is a very benignform of treatment in contrast to what Dr. Falk would usually use whichwould consist of irrigation and packing the area open.

When seen later, the abscess cavity had closed over. The patient advisedthat the visiting nurse on the weekends had difficulty putting acatheter into this cavity over Saturday and Sunday and in fact could notgain entrance of the catheter. Dr. Falk concluded that the cavity hadgranulated in from the "bottom up" but has done so much more rapidlythan he would have anticipated. In view of the fact that this is achronic cavity in a patient who has had a chronic and ongoing problem inthe pelvis, this is clearly an unanticipated result with a much morerapid and better resolution of a chronic abscess cavity thananticipated.

Dr. Falk has instructed the patient to call if he develops anytemperature subsequent to this. He has had a mild itching sensation overhis skin which Dr. Falk believes is probably a reaction to cold and forwhich he gave him an ointment to be applied daily.

CASE XXXV

Woman had a 9th and 12th nerve lesion, which was thought was locatedjust lateral to the base of the skull. It was also thought that she mayhave had metastases in the region of the dentoid process, and an MRIscan was undertaken to try and demonstrate this. It showed somewhatabnormalities in the appropriate area. A CT scan of the region wasunhelpful.

The patient then attended The Ontario Cancer Treatment and ResearchFoundation and was found to have very advanced malignant melanoma, andwas discharged from the hospital with a hopeless prognosis.

Much later the people of Ontario Cancer Treatment and ResearchFoundation were surprised and delighted to find that she had respondedunbelievably well to both positive mental imaging and to Dr. Falk'streatment. This involved hyperthermia and chemotherapy inthyaluronicacid. Dr. Falk used usual doses of Carboplastin and low dosesof Methotrexate in the hyaluronic acid.

Her chest now appears clear, and she has some persistent lesions inkidney and liver, but these may well be under control. During thesummer, her tongue got better, and no longer deviated to the left.However, during the last three or four weeks, things have deterioratedfrom that point of view.

On recent examination, the neurological examination was entirely normal,except for a deficit (incomplete) ingag on the left side of the pharynx,and a problem with some fasciculations and atrophy of the left side ofher tongue.

This patient has done remarkably wells.

Follow-Up

More recently this woman has been administered hyaluronic acid (300 mgdaily), NSAID and Vitamin C (50 gm daily). The patient appears now to beclear of tumour.

CASE XXXVI

This man has a mesothelioma following surgical resection and thenadjuvant treatment. It is now seven years since the initial diagnosis.In the spring of this year he developed a recurrence while in Florida.Although Dr. Falk has biopsied this three times, Dr. Falk has neverobtained cells diagnostic of malignancy. However, clinically thesituation is very clear from the CAT scan, liver function test andultrasound.

This patient has been treated with phloretin in hyaluronic acid, andheat to the area. Initially, he did not show a major response. However,on the last occasion he received no chemotherapy and only phloretin inhyaluronic acid with a higher dose of hyaluronic acid. He has had amajor response and has had major problems with accumulation of fluid,Dr. Falk believes, secondary to tumor breakdown. The tumor breakdown isclearly apparent on the sonographic assessment; here there is actualliquification of the tumor.

During his present stay, he was treated one day with hyperthermia andreceived phloridzin in hyaluronic acid. However, he required anadditional two days of treatment with Vitamin C in hyaluronic acid toassist in detoxification. He also received additional diuretics Lasix™(furosemide) with hyaluronic acid.

His creatinine which was 400 m mols/l has decreased to 155 y mols/l(kidney function tests--went from high to almost normal). Dr. Falk hasinstructed him regarding further management. Dr. Falk does not think thepatient will require major further therapy as Dr. Falk thinks themajority of this tumor has been destroyed, through his own immuneresponse, the antibody and the soluble mediators being allowed to enterinto the tumor by hyaluronic acid.

In July, 1990 moderate ascites (fluid in body) occurred. The patient wasgiven furosemide (Lasix™) and hyaluronic acid, indomethacin andhyaluronic acid. The patient's urine output increased substantially andthe problem cleared.

CASE XXXVII

A 37 year old female had a carcinoma of the cervix which was a classIIIB at the time of diagnosis. She was treated by radiation at the CrossCancer Centre, unsuccessfully, and developed further growth of the tumorwhich was diagnosed approximately 1 to 2 months after the radiotherapy.She was then seen by Dr. Walde at the Sault Ste. Marie hospital. Headministered epirubicin, cisplatinum at high doses and did produceregression of the tumor as assessed by intravaginal assessment andbiopsy, but apparently there was regrowth and worsening of the pain withpartial ureteric obstruction demonstrated as. shown by a CT scan of theabdomen and pelvis done Jun. 28, 1990.

At laparotomy, the patient had extensive tumor with major areas ofnecrosis but tumor extending to and involving the left common iliacartery and vein producing obstruction of the vein, the tumor wasconsidered not resertable for surgical cure because of its extent in thelateral true and false pelvis to the pelvic wall. This was assessed by aurological and two general oncological surgeons.

For this reason and because of imminent rectal obstruction, a colostomywas performed. In addition, the urological surgeon established an ilealconduit.

This patient was in excruciating pain continuously for several weeksprior to and after the surgical procedure. This necessitated high dosesof intravenous morphine with only partial control of the pain. On Jul.8th she was noted to have a major febrile reaction and a CAT scan thatday showed an abscess in the left pelvis. This was drained under CATscan localization and the patient was placed on systemic antibioticswith only slight improvement in her infectious symptoms.

She was brought to Dr. Falk on Wednesday, Jul. 11th. She received 1 gmof ampicillin through the draining catheter for the abscess with 500 mgof hyaluronic acid. In addition, she received 1 mg of ampicillinintravenously and ancef and flagyl systemically in 500 mg "LifeCore™"hyaluronic acid. She also received 100 mg of indomethacin with 500 mgLifeCore™ hyaluronic acid intravenously. Within 12 hours her pain haddramatically decreased, all infective symptoms were eliminated and thedrainage from the abscess cavity had almost stopped. Her massivelyenlarged left leg due to venous and lymphatic obstruction improved toalmost normal size within a 12 hour period of time.

The patient was subsequently treated further with the same regimen forthe next 3 days resulting in total relief of pain and continuedimprovement in her status, to the point where she could be dischargedfrom the hospital on Jul. 18th without anti-biotic therapy. Her systemicanalgesia with morphine agents had been eliminated. There was nohyperthermia and no cytosis chemotherapy and/or Oncostatin (phloretin)utilized in this patient. She received anti-oxidant therapy withhyaluronic acid concomitantly with the indomethacin-hyaluronic acid.This patient has demonstrated a very dramatic improvement emphasizingthat the indomethacin-hyaluronic acid is targeting specifically topathological tissue improving macrophage function at this site andallowing the body's immune system to perform appropriate tumordestruction.

CASE CASE XXXVIII

A male patient suffering from HIV (AIDS) was treated with indomethacin(NSAID), Vitamin C, interferon and DMSO and/or hyaluronic acid andunexpectedly the patient is steadily improving.

CASE XXXIX

A male patient'suffering from kyphosis suffered from constant back pain.Taking analgesics orally and rubbing back preparations onto his back,did little to alleviate the back pain. When NSAIDS in hyaluronic acid(sodium hyaluronate) were applied directly to the back, the back paineased and disappeared.

With indomethacin (dissolved in N-methyl glucamine) and naproxen bothdissolved in hyaluronic acid, the patient experienced side effects.However, with Toradol™ (the [+/-] form tromethamine salt of ketorolac--aprostaglandin biosynthesis inhibitor and analgesic andanti-inflammatory, the back pain eased and disappeared for some time andthere were no side effects.

CASE XL

This male patient was diagnosed with HIV (AIDS) and as a possible resultthereof, an undetermined neoplastic disorder in the lungs. Beforetreatment, the patient was near death; white cell count was 1.4×10⁹/liter. The patient was treated intravenously with indomethacin (300mg), Vitamin C (50 gm daily) and hyaluronic acid (sodium hyaluronate)(300 mg). After treatment, the patient's platelet count rose to 65×10⁹/liter. and his white cell count rose to 2×10⁹ /liter. His lymphocytesdoubled.

Further Tests (Animal)

Further tests were conducted on animals (rats) with the indicatedresults:

Enhanced Activity of Antibiotics with hyaluronic acid. A chronic abscessrat model was used. Sprague Dawley Rats were used. Pellets of bacteriawere inserted into each of the bellies of the rats and then the ratswere treated as indicated. In this model therapeutic activity ofgentamycin was compared to gentamycin in hyaluronic acid the resultsdemonstrate a statistically significant improvement by the combinationover the antibiotic alone. In this regard lower doses of ant-biotic inantibiotic refractory situations were required as a result of theantibiotic being administered with hyaluronic acid. Please refer to FIG.1/1 of the drawings.

In another animal test (Grafts from ACI strain rats (black) to LewisStrain rats (white)), enhancement of graft survival was found bycombinations of immune suppressors and hyaluronic acid (HA) administeredto the Lewis Strain rats. Graft survival depends in major part on theability to suppress graft rejection with immunosuppressive agentsoptimum activity of these agents is seldom achieved as they are notdelivered to the graft site in effective concentrations; combinations ofthe agent with hyaluronic acid overcomes this difficulty. Optimizationof immunosuppressive/graft survival activity by combination of specificagents with hyaluronic acid is achieved. A standard rat skin graftrejection model was used. Cyclosporin was the immunosuppressant used.The results indicate that hyaluronic acid significantly increasedcyclosporin induced graft survival.

    ______________________________________                                        GRAFT SURVIVAL OF DIFFERENT TREATMENTS                                          (JULY 12, 1990)                                                                 CYA + HA# days          CyA#  days                                        ______________________________________                                        1         20            7       20                                              2 19 8 20                                                                     3 19 9 20                                                                     4 20 10 19                                                                    5 19 11 19                                                                    6 20 12 20                                                                    13 21 20 19                                                                   14 19 21 17                                                                   15 18 22 14                                                                   16 20 23 14                                                                   17 20 24 14                                                                   18 20 25 19                                                                   19 20                                                                         mean 19.615 17.917                                                            SE 0.213 0.723                                                              ______________________________________                                         CyA + HA vs. CyA = P value,                                                   oneway ANOVA = <0.05 (=0.0287)                                                LSDMRT = <0.05                                                                CyA = Cyclosporin                                                             HA = Hyaluronic Acid                                                     

As many changes can be made to the invention without departing from thescope of the invention, it is intended that all material containedherein be interpreted as illustrative of the invention and not in alimiting sense.

The embodiments of the invention in which an exclusive property or privilege is claimed are as follows:
 1. A dosage amount of a pharmaceutical composition containing a suitable pharmaceutically acceptable excipient comprising:(1) a therapeutically effective amount of an agent to treat a disease or condition involving underperfused tissue and pathological tissue in humans; and (2) a form of hyaluronic acid selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof and combinations thereofcharacterized in that said dosage amount of said composition (a) is in a dosage form which is suitable for administration in humans; and (b) is in a form in which (i) component (1) is in an effective dosage amount to treat said disease or condition involving underperfused tissue and pathological tissue by penetration at the site to be treated; and (ii) component (2) is available to transport component (1) from the point of administration to the site to be treated, and which component (2) is in an effective non-toxic amount to facilitate the transport of component (1) upon administration from the site of administration to the site in need of treatment, through the tissue, at the site to be treated and through cell membranes into individual cells to be treated, wherein said amount of component (2) is sufficient to provide a dosage of 10 mg to 3000 mg of component (2) and wherein the molecular weight of component (2) is less than 750,000 daltons and greater than 150,000 daltons.
 2. The dosage of claim 1 wherein component (2) is sodium hyaluronate in an amount of between 10 mg and 1000 mg.
 3. The dosage of claim 1 or 2 wherein the agent is selected from the group consisting of free radical scavengers, ascorbic acid (Vitamin C), anti-cancer drugs, chemotherapeutic drugs, anti-viral drugs, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal drugs, detoxifying drugs, analgesics, bronchodilators, anti-bacterial drugs, antibiotic drugs for treatment of vascular ischemia, monoclonal antibodies, diuretics, immunosuppressants, lymphokines, α or β interferon, insulin, estrogen, progestogen, anti-metabolites, calcium channel blockers, drugs for treatment of psoriasis and combinations thereof.
 4. The dosage of claim 1 or 2 wherein the agent is selected from the group consisting of ascorbic acid, an anti-cancer drug, a non-steroidal anti-inflammatory drug, an antibiotic drug, a diuretic drug and combinations thereof.
 5. The dosage of claim 1, wherein the form of hyaluronic acid is sodium hyaluronate having a concentration of 2% by weight.
 6. The dosage of claim 1 or 2 wherein the agent is an anti-cancer drug.
 7. The dosage of claim 1 or 2 wherein the agent is an anti-viral drug.
 8. The dosage of claim 1 or 2 wherein the agent is an anti-fungal drug.
 9. The dosage of claim 1 or 2 wherein the agent is an analgesic drug.
 10. The dosage of claim 1 or 2 wherein the agent is a bronchodilator drug.
 11. The dosage of claim 1 or 2 wherein the agent is an anti-bacterial drug.
 12. The dosage of claim 1 or 2 wherein the agent is an antibiotic drug.
 13. The dosage of claim 1 or 2 wherein the agent is an anti-inflammatory drug.
 14. The dosage of claim 1 or 2 wherein the agent is a monoclonal antibody.
 15. The dosage of claim 1 or 2 wherein the agent is an immunosuppressant drug.
 16. The dosage of claim 1 or 2 wherein the agent is a lymphokine.
 17. The dosage of claim 16 wherein the lymphokine is interleukin-2.
 18. The dosage of claim 1 or 2 wherein the agent is interferon.
 19. The dosage of claim 1 or 2 wherein the agent is ascorbic acid (Vitamin C).
 20. The dosage of claim 1 or 2 wherein the agent is a free radical scavenger.
 21. The dosage of claim 1 or 2 wherein the agent is a chemotherapeutic drug.
 22. The dosage of claim 21 or 2 wherein the agent is a non-ionic surfactant drug.
 23. The dosage of claim 1 or 2 wherein the agent is a non-steroidal anti-inflammatory drug (NSAID).
 24. The dosage of claim 1 or 2 wherein the agent is a steroidal anti-inflammatory drug.
 25. The dosage of claim 1 or 2 wherein the agent is a detoxifying drug.
 26. The dosage of claim 1 or 2 wherein the agent is a diuretic drug.
 27. The dosage of claim 22 wherein the non-ionic surfactant is nonoxynol-9.
 28. The dosage of claim 22 wherein the non-ionic surfactant contains an ether or an amide linkage between the hydrophilic and hydrophobic portions of the surfactant.
 29. The dosage of claim 23 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, naproxen and ketorolac tromethamine salt and combinations thereof.
 30. The dosage of claim 26 wherein the diuretic is furosemide.
 31. The dosage of claim 1 or 2 wherein the method of administration is carried out intravenously, subcutaneously, intramuscularly or intratumourly.
 32. The dosage of claim 1 or 2 wherein the method of administration is carried out topically.
 33. The dosage of claim 1 or 2 wherein the agent is a surfactant selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride.
 34. The dosage of claim 1 or 2 wherein the agent is selected from estrogen replacement drugs.
 35. The dosage of claim 1 or 2 wherein the amount of the form of hyaluronic acid is between 50 mg and 350 mg.
 36. The dosage of claim 1, 2, or 5 wherein the dosage amount of the composition is formulated for topical administration.
 37. The dosage of claim 1 or 2 wherein the composition is formulated for intravenous, intramuscular or injectible administration.
 38. The dosage of claim 1 or 2 wherein the agent is a cytotoxic chemotherapeutic drug selected from the group consisting of adriamycin, methotrexate, mitomycin C, bleomycin, 5-Fluorouracil, novantrone, carbo and cis platinum, and combinations thereof.
 39. The dosage of claim 1 or 2 further comprising an effective amount of dimethyl sulfoxide.
 40. The dosage of claim 39 wherein the agent is selected from the group consisting of phloridzin, phloretin and 5-deoxyglucuronide of phloridzin, ascorbic acid and a non-steroidal anti-inflammatory drug.
 41. The dosage of claim 2 wherein the agent is selected from the group consisting of phloridzin, phloretin and 5-deoxyglucuronide of phloridzin.
 42. A dosage amount of a pharmaceutical composition for treating a condition or disease involving underperfused or pathological tissue comprising a therapeutically useful agent to a patient, the improvement which comprises additionally an amount of a form of hyaluronic acid selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid and combinations thereof, wherein the amount is between 10 mg and 3000 mg and is sufficient to facilitate passage of the agent and the form of hyaluronic acid to the underperfused or pathological tissue, and wherein the molecular weight of the form of hyaluronic acid is less than 750,000 daltons but greater than 150,000 daltons.
 43. The dosage of claim 42 wherein component (2) is sodium hyaluronate in an amount of between 10 mg and 1000 mg.
 44. The dosage of claim 42 or 43 wherein the agent is selected from the group consisting of free radical scavengers, ascorbic acid (Vitamin C), anti-cancer drugs, chemotherapeutic drugs, anti-viral drugs, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal drugs, detoxifying drugs, analgesics' bronchodilators, anti-bacterial drugs, antibiotic drugs for treatment of vascular ischemia, monoclonal antibodies, diuretics, immunosuppressants, lymphokines, α or β interferon, insulin, estrogen, progestogen, anti-metabolites, calcium channel blockers, drugs for treatment of psoriasis and combinations thereof.
 45. The dosage of claim 42 or 43 wherein the agent is selected from the group consisting of ascorbic acid, an anti-cancer drug, a non-steroidal anti-inflammatory drug, an antibiotic drug, a diuretic drug and combinations thereof.
 46. The dosage amount of claim 42 wherein the form of hyaluronic acid is sodium hyaluronate having a concentration of 2% by weight.
 47. The dosage of claim 42 or 43 wherein the agent is an anti-cancer drug.
 48. The dosage of claim 42 or 43 wherein the agent is an anti-viral drug.
 49. The dosage of claim 42 or 43 wherein the agent is an anti-fungal drug.
 50. The dosage of claim 42 or 43 wherein the agent is an analgesic drug.
 51. The dosage of claim 42 or 43 wherein the agent is a bronchodilator drug.
 52. The dosage of claim 42 or 43 wherein the agent is an anti-bacterial drug.
 53. The dosage of claim 42 or 43 wherein the agent is an antibiotic drug.
 54. The dosage of claim 42 or 43 wherein the agent is an anti-inflammatory drug.
 55. The dosage of claim 42 or 43 wherein the agent is a monoclonal antibody.
 56. The dosage of claim 42 or 43 wherein the agent is an immunosuppressant drug.
 57. The dosage of claim 42 or 43 wherein the agent is a lymphokine.
 58. The dosage of claim 57 wherein the lymphokine is interleukin-2.
 59. The dosage of claim 42 or 43 wherein the agent is interferon.
 60. The dosage of claim 42 or 43 wherein the agent is ascorbic acid (Vitamin C).
 61. The dosage of claim 42 or 43 wherein the agent is a free radical scavenger.
 62. The dosage of claim 42 or 43 wherein the agent is a chemotherapeutic drug.
 63. The dosage of claim 42 or 43 wherein the agent is a non-ionic surfactant drug.
 64. The dosage of claim 42 or 43 wherein the agent is a non-steroidal anti-inflammatory drug (NSAID).
 65. The dosage of claim 42 or 43 wherein the agent is a steroidal anti-inflammatory drug.
 66. The dosage of claim 42 or 43 wherein the agent is a detoxifying drug.
 67. The dosage of claim 42 or 43 wherein the agent is a diuretic drug.
 68. The dosage of claim 63 wherein the non-ionic surfactant is nonoxynol-9.
 69. The dosage of claim 63 wherein the non-ionic surfactant further comprises an ether or an amide linkage between the hydrophilic and hydrophobic portions of the surfactant.
 70. The dosage of claim 64 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, naproxen and ketorolac tromethamine salt and combinations thereof.
 71. The dosage of claim 67 wherein the diuretic is furosemide.
 72. The dosage of claim 42 or 43 wherein the method of administration is carried out intravenously, subcutaneously, intramuscularly or intratumourly.
 73. The dosage of claim 42 or 43 wherein the method of administration is carried out topically.
 74. The dosage of claim 42 or 43 wherein the agent is a surfactant selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride.
 75. The dosage of claim 42 or 43 wherein the agent is selected from estrogen replacement drugs.
 76. The dosage of claim 42 or 43 wherein the amount of the form of hyaluronic acid is between 50 mg and 350 mg.
 77. The dosage of claim 42, 43 or 46 wherein the dosage amount of the composition is formulated for topical administration.
 78. The dosage of claim 42 or 43 wherein the composition is formulated for intravenous, intramuscular or injectible administration.
 79. The dosage of claim 42 or 43 wherein the agent is a cytotoxic chemotherapeutic drug selected from the group consisting of adriamycin, methotrexate, mitomycin C, bleomycin, 5-Fluorouracil, novantrone, carbo and cis platinum, and combinations thereof.
 80. The dosage of claim 42 or 43 further comprising an effective amount of dimethyl sulfoxide.
 81. The dosage of claim 80 wherein the agent is selected from the group consisting of phloridzin, phloretin and 5-deoxyglucuronide of phloridzin, ascorbic acid and a non-steroidal anti-inflammatory drug.
 82. The dosage of claim 43 wherein the agent is selected from the group consisting of phloridzin, phloretin and 5-deoxyglucuronide of phloridzin.
 83. A dosage amount of a pharmaceutical composition in a suitable pharmaceutically acceptable excipient therefor comprising an agent selected from the group consisting of a medicinal agent and a therapeutic agent and combinations thereof, and a form of hyaluronic acid, the improvement comprising that the dosage amount of the composition is suitable for treating a condition or disease involving tissue selected from the group consisting of underperfused tissues and pathological tissue in a human, wherein a therapeutically effective amount of the agent is provided in combination with an effective amount of a form of hyaluronic acid selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts thereof and combinations thereof sufficient to facilitate transportation of the agent to the site to be treated through the tissue and cell membranes into individual cells to be treated, wherein said amount of the form of hyaluronic acid is present in an amount of between 10 mg and 1000 mg of the form of hyaluronic acid, and wherein the molecular weight of the form of hyaluronic acid is less than 750,000 daltons and greater than 150,000 daltons.
 84. A dosage amount of a pharmaceutical composition in a suitable pharmaceutically acceptable excipient therefor for treating a disease or condition involving tissue selected from the group consisting of underperfused and pathological tissue in a human comprising an effective amount of an agent selected from the group consisting of a free radical scavenger, ascorbic acid, Vitamin C, an anti-cancer agent, chemotherapeutic agent, anti-viral agents, non-steroidal anti-inflammatory drugs (NSAIDS), steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents, analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia monoclonal antibody, diuretics, immunosuppressants, lymphokines, α and β interferon, insulin, estrogen, progestogen, anti-metabolites, calcium channel blockers, drugs for the treatment of psoriasis and combinations thereof and an effective amount of a form of hyaluronic acid selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts thereof and combinations thereof sufficient to facilitate the agent's penetration through tissue including scar tissue, at site to be treated, through cell membranes into individual cells to be treated, wherein said amount of the form of hyaluronic acid is sufficient to provide a dosage between 10 mg and 1000 mg of the form of hyaluronic acid and wherein the molecular weight of the form of hyaluronic acid is less than 750,000 daltons and greater than 150,000 daltons, with the proviso that if the agent selected is phloretin, it is solubilized.
 85. The dosage of claim 83 or 84 wherein the agent is selected from the group consisting of a free radical scavenger, ascorbic acid, Vitamin C, an anti-cancer agent, chemotherapeutic agent, anti-viral agents, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal agent, detoxifying agents, analgesic, bronchodilator, anti-bacterial agent, antibiotics, drugs for the treatment of vascular ischemia monoclonal antibody, diuretics, immunosuppressants, lymphokines, α and β interferon, insulin, estrogen, progestogen, anti-metabolites, calcium channel blockers, drugs for the treatment of psoriasis and combinations thereof.
 86. The dosage of claim 83 or 84 wherein the dosage amount of the composition is formulated for topical administration.
 87. The dosage of claim 83 or 84 wherein the composition is formulated for intravenous, intramuscular or subcutaneous injectible, intra-arterial, intradermal, intraperitoneal, or intrapleural administration.
 88. The dosage of claim 83 or 84 wherein the form of hyaluronic acid is utilized in an amount of 100 mg.
 89. The dosage of claim 83 or 84 wherein the form of hyaluronic acid is utilized in an amount in excess of 200 mg.
 90. The dosage of claim 83 or 84 wherein the form of hyaluronic acid is utilized in an amount in excess of 350 mg.
 91. The dosage of claim 83 or 84 wherein the form of hyaluronic acid is utilized at a dose less than 3000 mg.
 92. A dosage of a pharmaceutical composition comprising an effective amount of an agent selected from the group consisting of phloridzin, phloretin, and 5-deoxyglucuronide of phloridzin; Vitamin C; and a non-steroidal anti-inflammatory drug, and combinations thereof to competitively block glucose transport in neoplastic cells and an amount of a form of hyaluronic acid selected from the group consisting of hyaluronic acid and pharmaceutically acceptable salts thereof and combinations thereof sufficient to facilitate the agent's penetration through tissue at a site to be treated, through cell membranes into individual cells to be treated and where phloretin is the selected agent, it is solubilized by a solubilizing agent, wherein said amount of the form of hyaluronic acid is sufficient to provide a dosage of 10 mg to 1000 mg of the form of hyaluronic acid and wherein the molecular weight of the form of hyaluronic acid is less than 750,000 daltons and greater than 150,000 daltons. 